rs72648904

Variant names:

• chr2-178748924-G-A
• rs72648904
• NM_133379.5:c.13476C>T

Variant summary

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

The NM_133379.5(TTN):​c.13476C>T​(p.Asp4492Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,612,396 control chromosomes in the GnomAD database, including 967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (48 hom., cov: 32)
  • Exomes 𝑓: 0.032 (919 hom.)
• Consequence: TTN NM_133379.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.757

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=-0.82).
• BP6: Variant 2-178748924-G-A is Benign according to our data. Variant chr2-178748924-G-A is described in ClinVar as [Benign]. Clinvar id is 47756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178748924-G-A is described in Lovd as [Benign]. Variant chr2-178748924-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.757 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0229 (3475/152040) while in subpopulation NFE AF= 0.0337 (2287/67904). AF 95% confidence interval is 0.0325. There are 48 homozygotes in gnomad4. There are 1710 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 48 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_133379.5	c.13476C>T	p.Asp4492Asp	synonymous_variant	Exon 46 of 46	ENST00000360870.10	NP_596870.2
TTN	NM_001267550.2	c.11311+4200C>T		intron_variant	Intron 47 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10	c.13476C>T	p.Asp4492Asp	synonymous_variant	Exon 46 of 46	5	NM_133379.5	ENSP00000354117.4
TTN	ENST00000589042.5	c.11311+4200C>T		intron_variant	Intron 47 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3477 AN: 151922 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.00708

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0386

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0331

GnomAD3 exomes AF: 0.0228 AC: 5703 AN: 250186 Hom.: 83 AF XY: 0.0235 AC XY: 3180 AN XY: 135280

Gnomad AFR exome AF: 0.00678

Gnomad AMR exome AF: 0.0159

Gnomad ASJ exome AF: 0.00815

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0103

Gnomad FIN exome AF: 0.0361

Gnomad NFE exome AF: 0.0327

Gnomad OTH exome AF: 0.0285

GnomAD4 exome AF: 0.0323 AC: 47196 AN: 1460356 Hom.: 919 Cov.: 35 AF XY: 0.0316 AC XY: 22956 AN XY: 726492

Gnomad4 AFR exome AF: 0.00518

Gnomad4 AMR exome AF: 0.0170

Gnomad4 ASJ exome AF: 0.00878

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0107

Gnomad4 FIN exome AF: 0.0325

Gnomad4 NFE exome AF: 0.0374

Gnomad4 OTH exome AF: 0.0287

GnomAD4 genome AF: 0.0229 AC: 3475 AN: 152040 Hom.: 48 Cov.: 32 AF XY: 0.0230 AC XY: 1710 AN XY: 74340

Gnomad4 AFR AF: 0.00703

Gnomad4 AMR AF: 0.0206

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.0386

Gnomad4 NFE AF: 0.0337

Gnomad4 OTH AF: 0.0323

Alfa AF: 0.0277 Hom.: 32

Bravo AF: 0.0217

Asia WGS AF: 0.00289 AC: 10 AN: 3476

EpiCase AF: 0.0343

EpiControl AF: 0.0333

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Jan 13, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 16, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:4

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.79
DANN	Benign	0.42

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: rs72648904; hg19: chr2-179613651;