rs182428755

chr2-178675734-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):c.34474C>A(p.Pro11492Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00601 in 1,437,438 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (29 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.672

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]

LOC124906100 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0054418445).
• BP6: Variant 2-178675734-G-T is Benign according to our data. Variant chr2-178675734-G-T is described in ClinVar as [Benign]. Clinvar id is 238748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178675734-G-T is described in Lovd as [Benign]. Variant chr2-178675734-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00363 (551/151892) while in subpopulation NFE AF= 0.00494 (335/67866). AF 95% confidence interval is 0.0045. There are 2 homozygotes in gnomad4. There are 262 alleles in male gnomad4 subpopulation. 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.34474C>A	p.Pro11492Thr	missense_variant	149/363	ENST00000589042.5
LOC124906100	XR_007087318.1	n.2185+31233G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.34474C>A	p.Pro11492Thr	missense_variant	149/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.503-58770G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 551 AN: 151774 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00270

Gnomad ASJ AF: 0.0312

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00492

Gnomad OTH AF: 0.00481

GnomAD3 exomes AF: 0.00449 AC: 324 AN: 72170 Hom.: 2 AF XY: 0.00443 AC XY: 166 AN XY: 37470

Gnomad AFR exome AF: 0.000710

Gnomad AMR exome AF: 0.00326

Gnomad ASJ exome AF: 0.0282

Gnomad EAS exome AF: 0.000132

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00572

Gnomad OTH exome AF: 0.00563

GnomAD4 exome AF: 0.00629 AC: 8086 AN: 1285546 Hom.: 29 Cov.: 30 AF XY: 0.00615 AC XY: 3847 AN XY: 625506

Gnomad4 AFR exome AF: 0.000990

Gnomad4 AMR exome AF: 0.00286

Gnomad4 ASJ exome AF: 0.0314

Gnomad4 EAS exome AF: 0.0000289

Gnomad4 SAS exome AF: 0.000241

Gnomad4 FIN exome AF: 0.000207

Gnomad4 NFE exome AF: 0.00669

Gnomad4 OTH exome AF: 0.00728

GnomAD4 genome AF: 0.00363 AC: 551 AN: 151892 Hom.: 2 Cov.: 32 AF XY: 0.00353 AC XY: 262 AN XY: 74272

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00269

Gnomad4 ASJ AF: 0.0312

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00494

Gnomad4 OTH AF: 0.00476

Alfa AF: 0.00409 Hom.: 1

Bravo AF: 0.00389

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00804 AC: 31

ExAC AF: 0.00296 AC: 74

Asia WGS AF: 0.000577 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 27, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TTN: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

TTN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2019

This variant is classified as 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	18
Dann	Benign	0.70
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0054	T
MutationTaster	Benign	1.0	D;D;D;D;D;N
Vest4		0.23
MVP		0.74
GERP RS		6.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs182428755; hg19: chr2-179540461;