rs147580753

chr2-178590403-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):c.61322A>G(p.Asn20441Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,606,986 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 1.85

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0068585575).
• BP6: Variant 2-178590403-T-C is Benign according to our data. Variant chr2-178590403-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47172.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=6}. Variant chr2-178590403-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00108 (165/152200) while in subpopulation AFR AF= 0.0039 (162/41566). AF 95% confidence interval is 0.00341. There are 2 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.61322A>G	p.Asn20441Ser	missense_variant	304/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.3189-736T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.61322A>G	p.Asn20441Ser	missense_variant	304/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.417-7193T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 165 AN: 152082 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000260 AC: 63 AN: 241882 Hom.: 1 AF XY: 0.000176 AC XY: 23 AN XY: 130910

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.000178

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000101 AC: 147 AN: 1454786 Hom.: 1 Cov.: 37 AF XY: 0.0000940 AC XY: 68 AN XY: 723040

Gnomad4 AFR exome AF: 0.00385

Gnomad4 AMR exome AF: 0.000159

Gnomad4 ASJ exome AF: 0.0000391

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152200 Hom.: 2 Cov.: 33 AF XY: 0.000995 AC XY: 74 AN XY: 74396

Gnomad4 AFR AF: 0.00390

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000247 Hom.: 0

Bravo AF: 0.00120

ESP6500AA AF: 0.00261 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000397 AC: 48

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 07, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 09, 2022	Variant summary: TTN c.53618A>G (p.Asn17873Ser) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 273254 control chromosomes (gnomAD), predominantly at a frequency of 0.0037 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.53618A>G in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed the variant since 2014: two classify the variant as of uncertain significance and three as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 22, 2013	Asn17873Ser in exon 253 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (10/3832) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS/; dbSNP rs147580753) and in 1/176 chromosomes from a population of Yoruba individuals by the 1000 Genomes project (dbSNP rs147580753 ). Asn17873Ser in exon 253 of TTN (rs147580753; allele frequency = 0.3%, 10/38 32) ** -

TTN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 10, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	15
Dann	Benign	0.82
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.044
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D;D;.;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0069	T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.57	D;D;D;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.6	D;D;.;.;D;D;.
REVEL	Benign	0.13
Sift	Benign	0.79	T;T;.;.;T;T;.
Polyphen		0.10	.;.;.;B;.;.;B
Vest4		0.23
MVP		0.14
MPC		0.096
ClinPred		0.032	T
GERP RS		3.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs147580753; hg19: chr2-179455130;