NM_001267550.2:c.38336T>C

Variant names:

• chr2-178654252-A-G
• rs2099130
• NM_001267550.2:c.38336T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001267550.2(TTN):​c.38336T>C​(p.Val12779Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000981 in 1,598,794 control chromosomes in the GnomAD database, including 78 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (7 hom., cov: 22)
  • Exomes 𝑓: 0.00079 (71 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.147
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073044896).
• BP6: Variant 2-178654252-A-G is Benign according to our data. Variant chr2-178654252-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.38336T>C	p.Val12779Ala	missense	Exon 193 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.34523-1711T>C		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.31742-1711T>C		intron	N/A	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.38336T>C	p.Val12779Ala	missense	Exon 193 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.38336T>C	p.Val12779Ala	missense	Exon 193 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.38060T>C	p.Val12687Ala	missense	Exon 191 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 421 AN: 148924 Hom.: 7 Cov.: 22

Gnomad AFR AF: 0.00597

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00325

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00624

Gnomad SAS AF: 0.00389

Gnomad FIN AF: 0.00106

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000991

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00145 AC: 347 AN: 238830 AF XY: 0.00142

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.00155

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00321

Gnomad FIN exome AF: 0.000616

Gnomad NFE exome AF: 0.000641

Gnomad OTH exome AF: 0.00186

GnomAD4 exome AF: 0.000790 AC: 1146 AN: 1449762 Hom.: 71 Cov.: 32 AF XY: 0.000846 AC XY: 610 AN XY: 721074

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00290 AC: 96 AN: 33152

American (AMR) AF: 0.00203 AC: 87 AN: 42798

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26092

East Asian (EAS) AF: 0.00762 AC: 302 AN: 39620

South Asian (SAS) AF: 0.00279 AC: 233 AN: 83538

European-Finnish (FIN) AF: 0.000993 AC: 49 AN: 49362

Middle Eastern (MID) AF: 0.00141 AC: 8 AN: 5666

European-Non Finnish (NFE) AF: 0.000269 AC: 299 AN: 1109492

Other (OTH) AF: 0.00118 AC: 71 AN: 60042

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00283 AC: 422 AN: 149032 Hom.: 7 Cov.: 22 AF XY: 0.00314 AC XY: 228 AN XY: 72506

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00601 AC: 244 AN: 40626

American (AMR) AF: 0.00324 AC: 46 AN: 14182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00606 AC: 31 AN: 5114

South Asian (SAS) AF: 0.00389 AC: 17 AN: 4366

European-Finnish (FIN) AF: 0.00106 AC: 11 AN: 10358

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000991 AC: 67 AN: 67622

Other (OTH) AF: 0.00190 AC: 4 AN: 2100

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00111 Hom.: 1

ExAC AF: 0.00203 AC: 242

EpiCase AF: 0.00115

EpiControl AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 25, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN: BS2

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.76
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0073	T
PhyloP100		0.15
Vest4		0.16
MVP		0.84
GERP RS		0.92
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs2099130; hg19: chr2-179518979; COSMIC: COSV60173556; COSMIC: COSV60173556;