chr2-178748537-C-T

Variant names:

• chr2-178748537-C-T
• rs77419653
• NM_001267550.2:c.11311+4587G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_133379.5(TTN):​c.13863G>A​(p.Met4621Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,612,976 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (58 hom.)
• Consequence: TTN NM_133379.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0130
• Publications: 10 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053555667).
• BP6: Variant 2-178748537-C-T is Benign according to our data. Variant chr2-178748537-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 192176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00413 (628/152034) while in subpopulation EAS AF = 0.0295 (152/5158). AF 95% confidence interval is 0.0256. There are 11 homozygotes in GnomAd4. There are 412 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133379.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.11311+4587G>A		intron	N/A	NP_001254479.2
	TTN	NM_133379.5		c.13863G>A	p.Met4621Ile	missense	Exon 46 of 46	NP_596870.2
	TTN	NM_001256850.1		c.10360+4587G>A		intron	N/A	NP_001243779.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.11311+4587G>A		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.11311+4587G>A		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.11035+4587G>A		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00413 AC: 628 AN: 151916 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000723

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0294

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0352

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00648 AC: 1614 AN: 249206 AF XY: 0.00599

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0309

Gnomad FIN exome AF: 0.0363

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00461

GnomAD4 exome AF: 0.00244 AC: 3568 AN: 1460942 Hom.: 58 Cov.: 35 AF XY: 0.00240 AC XY: 1746 AN XY: 726790

African (AFR) AF: 0.0000299 AC: 1 AN: 33436

American (AMR) AF: 0.00172 AC: 77 AN: 44694

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

East Asian (EAS) AF: 0.0228 AC: 903 AN: 39658

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86230

European-Finnish (FIN) AF: 0.0366 AC: 1952 AN: 53292

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.000355 AC: 395 AN: 1111438

Other (OTH) AF: 0.00333 AC: 201 AN: 60342

GnomAD4 genome AF: 0.00413 AC: 628 AN: 152034 Hom.: 11 Cov.: 32 AF XY: 0.00554 AC XY: 412 AN XY: 74324

African (AFR) AF: 0.000217 AC: 9 AN: 41516

American (AMR) AF: 0.000722 AC: 11 AN: 15228

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

East Asian (EAS) AF: 0.0295 AC: 152 AN: 5158

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.0352 AC: 373 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00115 AC: 78 AN: 67934

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00177 Hom.: 10

Bravo AF: 0.00196

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00615 AC: 747

Asia WGS AF: 0.00520 AC: 18 AN: 3474

EpiCase AF: 0.000328

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.76
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.013
PROVEAN	Benign	0.17	N
REVEL	Benign	0.056
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.44	T
Polyphen		0.0010	B
Vest4		0.34
MutPred		0.30		Gain of catalytic residue at M4621 (P = 0.0081)
MVP		0.22
ClinPred		0.037	T
GERP RS		0.34
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: rs77419653; hg19: chr2-179613264; COSMIC: COSV60085365; COSMIC: COSV60085365;