chr2-178662395-T-C

Variant names:

• chr2-178662395-T-C
• rs146313925
• NM_001267550.2:c.36982A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001267550.2(TTN):​c.36982A>G​(p.Thr12328Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 16)
  • Exomes 𝑓: 0.00022 (121 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -1.64
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08462763).

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.36982A>G	p.Thr12328Ala	missense	Exon 177 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.34354+571A>G		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.31573+571A>G		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.36982A>G	p.Thr12328Ala	missense	Exon 177 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.36982A>G	p.Thr12328Ala	missense	Exon 177 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.36706A>G	p.Thr12236Ala	missense	Exon 175 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000168 AC: 21 AN: 125274 Hom.: 0 Cov.: 16

Gnomad AFR AF: 0.000248

Gnomad AMI AF: 0.00173

Gnomad AMR AF: 0.000176

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000312

Gnomad SAS AF: 0.000360

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000115

Gnomad OTH AF: 0.000590

GnomAD2 exomes AF: 0.00 AC: 0 AN: 202082 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000224 AC: 299 AN: 1336642 Hom.: 121 Cov.: 31 AF XY: 0.000270 AC XY: 179 AN XY: 662308

African (AFR) AF: 0.000135 AC: 4 AN: 29536

American (AMR) AF: 0.00320 AC: 119 AN: 37162

Ashkenazi Jewish (ASJ) AF: 0.0000822 AC: 2 AN: 24322

East Asian (EAS) AF: 0.0000682 AC: 2 AN: 29332

South Asian (SAS) AF: 0.00169 AC: 110 AN: 65142

European-Finnish (FIN) AF: 0.000195 AC: 7 AN: 35820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3766

European-Non Finnish (NFE) AF: 0.0000426 AC: 45 AN: 1056704

Other (OTH) AF: 0.000182 AC: 10 AN: 54858

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000168 AC: 21 AN: 125348 Hom.: 0 Cov.: 16 AF XY: 0.000149 AC XY: 9 AN XY: 60380

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

African (AFR) AF: 0.000247 AC: 8 AN: 32358

American (AMR) AF: 0.000176 AC: 2 AN: 11356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3012

East Asian (EAS) AF: 0.000312 AC: 1 AN: 3202

South Asian (SAS) AF: 0.000360 AC: 1 AN: 2776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.000115 AC: 7 AN: 61056

Other (OTH) AF: 0.000588 AC: 1 AN: 1702

⚠️ 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: 0.0100 Hom.: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Dec 23, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Uncertain:1

Aug 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.093
DANN	Benign	0.62
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.00048	T
MetaRNN	Benign	0.085	T
PhyloP100		-1.6
Vest4		0.025
MVP		0.54
GERP RS		-2.1
Mutation Taster		=98/2	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: rs146313925; hg19: chr2-179527122;