rs72955212

chr2-178756457-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):c.11019C>T(p.Cys3673=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,613,732 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (22 hom., cov: 32)
  • Exomes 𝑓: 0.014 (163 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.0220

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-178756457-G-A is Benign according to our data. Variant chr2-178756457-G-A is described in ClinVar as [Benign]. Clinvar id is 47850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178756457-G-A is described in Lovd as [Benign]. Variant chr2-178756457-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.022 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0102 (1554/152276) while in subpopulation NFE AF= 0.0156 (1064/68018). AF 95% confidence interval is 0.0149. There are 22 homozygotes in gnomad4. There are 743 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.11019C>T	p.Cys3673=	synonymous_variant	46/363	ENST00000589042.5
TTN	NM_133379.5	c.10303+2527C>T		intron_variant		ENST00000360870.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.11019C>T	p.Cys3673=	synonymous_variant	46/363	5	NM_001267550.2	P1
TTN	ENST00000360870.10	c.10303+2527C>T		intron_variant		5	NM_133379.5
TTN-AS1	ENST00000659121.1	n.1280+135G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1555 AN: 152158 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0236

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.0111 AC: 2750 AN: 248618 Hom.: 32 AF XY: 0.0108 AC XY: 1461 AN XY: 134888

Gnomad AFR exome AF: 0.00245

Gnomad AMR exome AF: 0.00453

Gnomad ASJ exome AF: 0.00607

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.0243

Gnomad NFE exome AF: 0.0166

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0139 AC: 20321 AN: 1461456 Hom.: 163 Cov.: 33 AF XY: 0.0135 AC XY: 9808 AN XY: 727030

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00463

Gnomad4 ASJ exome AF: 0.00650

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.0248

Gnomad4 NFE exome AF: 0.0159

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.0102 AC: 1554 AN: 152276 Hom.: 22 Cov.: 32 AF XY: 0.00998 AC XY: 743 AN XY: 74462

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.00550

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0236

Gnomad4 NFE AF: 0.0156

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.0137 Hom.: 11

Bravo AF: 0.00872

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0137

EpiControl AF: 0.0146

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 05, 2019	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 12, 2011	Silent variant: classified as benign based on population frequency of >1% -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -

Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

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

- -

Early-onset myopathy with fatal cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Tibial muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.061
Dann	Benign	0.72

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: rs72955212; hg19: chr2-179621184; COSMIC: COSV60293610; COSMIC: COSV60293610;