rs75785339

Positions:

• chr2-178748420-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133379.5(TTN):​c.13980C>G​(p.His4660Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,613,078 control chromosomes in the GnomAD database, including 628 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H4660Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.036 (331 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (297 hom.)
• Consequence: TTN NM_133379.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.771

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017023385).
• BP6: Variant 2-178748420-G-C is Benign according to our data. Variant chr2-178748420-G-C is described in ClinVar as [Benign]. Clinvar id is 47766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178748420-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_133379.5	c.13980C>G	p.His4660Gln	missense_variant	46/46	ENST00000360870.10
TTN	NM_001267550.2	c.11311+4704C>G		intron_variant		ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000360870.10	c.13980C>G	p.His4660Gln	missense_variant	46/46	5	NM_133379.5
TTN	ENST00000589042.5	c.11311+4704C>G		intron_variant		5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.1223+5450G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0355 AC: 5387 AN: 151896 Hom.: 331 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000383

Gnomad OTH AF: 0.0321

GnomAD3 exomes AF: 0.00876 AC: 2185 AN: 249420 Hom.: 107 AF XY: 0.00641 AC XY: 865 AN XY: 134890

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.00472

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000312

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00360 AC: 5261 AN: 1461064 Hom.: 297 Cov.: 35 AF XY: 0.00304 AC XY: 2208 AN XY: 726864

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.00551

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000132

Gnomad4 OTH exome AF: 0.00893

GnomAD4 genome AF: 0.0356 AC: 5414 AN: 152014 Hom.: 331 Cov.: 32 AF XY: 0.0335 AC XY: 2489 AN XY: 74322

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000383

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.00547 Hom.: 29

Bravo AF: 0.0405

ESP6500AA AF: 0.119 AC: 523

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.0112 AC: 1365

Asia WGS AF: 0.00895 AC: 31 AN: 3476

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 11, 2012	His4660Gln in exon 45A of TTN: This variant is not expected to have clinical sig nificance because it has been identified in 12.1% (452/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs75785339). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.2
DANN	Benign	0.45
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PROVEAN	Benign	0.48	N
REVEL	Benign	0.032
Sift	Benign	1.0	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.035
MutPred		0.18		Gain of loop (P = 0.069);
ClinPred		0.0012	T
GERP RS		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs75785339; hg19: chr2-179613147;