2-178547725-C-T

Variant names:

• chr2-178547725-C-T
• rs67665715
• NM_001267550.2:c.93901G>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.93901G>A​(p.Val31301Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00658 in 1,613,860 control chromosomes in the GnomAD database, including 521 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V31301F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.033 (267 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (254 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 1.01
• Publications: 8 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=0.0017256737).
• BP6: Variant 2-178547725-C-T is Benign according to our data. Variant chr2-178547725-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 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.93901G>A	p.Val31301Ile	missense	Exon 339 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.88978G>A	p.Val29660Ile	missense	Exon 289 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.86197G>A	p.Val28733Ile	missense	Exon 288 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.93901G>A	p.Val31301Ile	missense	Exon 339 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.93745G>A	p.Val31249Ile	missense	Exon 337 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.93625G>A	p.Val31209Ile	missense	Exon 337 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4951 AN: 152112 Hom.: 265 Cov.: 33

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.0216

GnomAD2 exomes AF: 0.00858 AC: 2136 AN: 248902 AF XY: 0.00655

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.00556

Gnomad ASJ exome AF: 0.00557

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000736

Gnomad OTH exome AF: 0.00414

GnomAD4 exome AF: 0.00387 AC: 5658 AN: 1461630 Hom.: 254 Cov.: 34 AF XY: 0.00338 AC XY: 2458 AN XY: 727106

African (AFR) AF: 0.119 AC: 3967 AN: 33466

American (AMR) AF: 0.00608 AC: 272 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00696 AC: 182 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53402

Middle Eastern (MID) AF: 0.00624 AC: 36 AN: 5768

European-Non Finnish (NFE) AF: 0.000613 AC: 681 AN: 1111824

Other (OTH) AF: 0.00820 AC: 495 AN: 60370

GnomAD4 genome AF: 0.0326 AC: 4966 AN: 152230 Hom.: 267 Cov.: 33 AF XY: 0.0317 AC XY: 2357 AN XY: 74422

African (AFR) AF: 0.112 AC: 4648 AN: 41530

American (AMR) AF: 0.0128 AC: 195 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68008

Other (OTH) AF: 0.0213 AC: 45 AN: 2110

Alfa AF: 0.0127 Hom.: 210

Bravo AF: 0.0376

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.101 AC: 395

ESP6500EA AF: 0.000961 AC: 8

ExAC AF: 0.0106 AC: 1279

Asia WGS AF: 0.00722 AC: 26 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	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	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.4
DANN	Benign	0.76
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.86	L
PhyloP100		1.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.035
MPC		0.069
ClinPred		0.00060	T
GERP RS		-2.3
Mutation Taster		=99/1	polymorphism (auto)

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: rs67665715; hg19: chr2-179412452;