chr2-178665800-A-G

Variant names:

• chr2-178665800-A-G
• rs572783607
• NM_001267550.2:c.35876-9T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001267550.2(TTN):​c.35876-9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,259,746 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00097 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: TTN NM_001267550.2 intron
• Scores: Splicing: ADA: 0.001202
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.476
• Publications: 0 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 (BayesDel_noAF=-0.52).
• BP6: Variant 2-178665800-A-G is Benign according to our data. Variant chr2-178665800-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 413136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000966 (147/152230) while in subpopulation AFR AF = 0.0033 (137/41554). AF 95% confidence interval is 0.00285. There are 1 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.35876-9T>C		intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.34265-2745T>C		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.31484-2745T>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.35876-9T>C		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.35876-9T>C		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.35600-9T>C		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000966 AC: 147 AN: 152112 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000341 AC: 6 AN: 17580 AF XY: 0.000328

Gnomad AFR exome AF: 0.00387

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000831 AC: 92 AN: 1107516 Hom.: 0 Cov.: 22 AF XY: 0.0000569 AC XY: 30 AN XY: 526856

African (AFR) AF: 0.00338 AC: 81 AN: 23938

American (AMR) AF: 0.000167 AC: 2 AN: 11944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15476

East Asian (EAS) AF: 0.00 AC: 0 AN: 29644

South Asian (SAS) AF: 0.00 AC: 0 AN: 25444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3050

European-Non Finnish (NFE) AF: 0.00000215 AC: 2 AN: 929336

Other (OTH) AF: 0.000153 AC: 7 AN: 45686

GnomAD4 genome AF: 0.000966 AC: 147 AN: 152230 Hom.: 1 Cov.: 32 AF XY: 0.000967 AC XY: 72 AN XY: 74424

African (AFR) AF: 0.00330 AC: 137 AN: 41554

American (AMR) AF: 0.000524 AC: 8 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000693 Hom.: 0

Bravo AF: 0.00103

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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

TTN-related disorder Benign:1

Jun 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Mar 08, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.2
DANN	Benign	0.58
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.030
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.54		Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs572783607; hg19: chr2-179530527;