chr2-178549591-C-T

Variant names:

• chr2-178549591-C-T
• rs747122
• NM_001267550.2:c.92131G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.92131G>A​(p.Val30711Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0589 in 1,612,856 control chromosomes in the GnomAD database, including 6,393 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1791 hom., cov: 33)
  • Exomes 𝑓: 0.053 (4602 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.919
• Publications: 28 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]

ENSG00000270277 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014583766).
• BP6: Variant 2-178549591-C-T is Benign according to our data. Variant chr2-178549591-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.92131G>A	p.Val30711Met	missense	Exon 338 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.87208G>A	p.Val29070Met	missense	Exon 288 of 313	NP_001243779.1
	TTN	NM_133378.4		c.84427G>A	p.Val28143Met	missense	Exon 287 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.92131G>A	p.Val30711Met	missense	Exon 338 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.91975G>A	p.Val30659Met	missense	Exon 336 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.91855G>A	p.Val30619Met	missense	Exon 336 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17373 AN: 152104 Hom.: 1768 Cov.: 33

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.0245

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0588

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.0900

GnomAD2 exomes AF: 0.0928 AC: 22905 AN: 246802 AF XY: 0.0882

Gnomad AFR exome AF: 0.259

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.0354

Gnomad EAS exome AF: 0.0275

Gnomad FIN exome AF: 0.0577

Gnomad NFE exome AF: 0.0334

Gnomad OTH exome AF: 0.0686

GnomAD4 exome AF: 0.0531 AC: 77583 AN: 1460634 Hom.: 4602 Cov.: 35 AF XY: 0.0551 AC XY: 40042 AN XY: 726434

African (AFR) AF: 0.268 AC: 8981 AN: 33456

American (AMR) AF: 0.204 AC: 9119 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 948 AN: 26114

East Asian (EAS) AF: 0.0138 AC: 547 AN: 39672

South Asian (SAS) AF: 0.174 AC: 14996 AN: 86206

European-Finnish (FIN) AF: 0.0589 AC: 3142 AN: 53378

Middle Eastern (MID) AF: 0.0578 AC: 333 AN: 5760

European-Non Finnish (NFE) AF: 0.0320 AC: 35546 AN: 1111010

Other (OTH) AF: 0.0658 AC: 3971 AN: 60334

GnomAD4 genome AF: 0.115 AC: 17448 AN: 152222 Hom.: 1791 Cov.: 33 AF XY: 0.120 AC XY: 8900 AN XY: 74430

African (AFR) AF: 0.256 AC: 10632 AN: 41490

American (AMR) AF: 0.176 AC: 2687 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3470

East Asian (EAS) AF: 0.0247 AC: 128 AN: 5182

South Asian (SAS) AF: 0.177 AC: 853 AN: 4830

European-Finnish (FIN) AF: 0.0588 AC: 624 AN: 10612

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0315 AC: 2141 AN: 68032

Other (OTH) AF: 0.0891 AC: 188 AN: 2110

Alfa AF: 0.0554 Hom.: 2739

Bravo AF: 0.127

TwinsUK AF: 0.0297 AC: 110

ALSPAC AF: 0.0288 AC: 111

ESP6500AA AF: 0.261 AC: 971

ESP6500EA AF: 0.0308 AC: 252

ExAC AF: 0.0902 AC: 10896

Asia WGS AF: 0.128 AC: 445 AN: 3476

EpiCase AF: 0.0314

EpiControl AF: 0.0325

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.94
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.92
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D
Polyphen		0.97	D
Vest4		0.21
MPC		0.29
ClinPred		0.026	T
GERP RS		5.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs747122; hg19: chr2-179414318; COSMIC: COSV59942992; COSMIC: COSV59942992;