chr2-178735576-G-C

Variant names:

• chr2-178735576-G-C
• rs72648925
• NM_001267550.2:c.14870C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.14870C>G​(p.Thr4957Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,612,960 control chromosomes in the GnomAD database, including 22 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T4957P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (14 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:20
• Conservation: PhyloP100: 2.04
• Publications: 17 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010286361).
• BP6: Variant 2-178735576-G-C is Benign according to our data. Variant chr2-178735576-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46594.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00287 (437/152286) while in subpopulation AMR AF = 0.00484 (74/15294). AF 95% confidence interval is 0.00395. There are 8 homozygotes in GnomAd4. There are 194 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

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.14870C>G	p.Thr4957Ser	missense	Exon 50 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.13919C>G	p.Thr4640Ser	missense	Exon 48 of 313	NP_001243779.1
	TTN	NM_133378.4		c.11138C>G	p.Thr3713Ser	missense	Exon 47 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.14870C>G	p.Thr4957Ser	missense	Exon 50 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.14870C>G	p.Thr4957Ser	missense	Exon 50 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.14594C>G	p.Thr4865Ser	missense	Exon 48 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 437 AN: 152168 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00307

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00292 AC: 722 AN: 247488 AF XY: 0.00293

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.00516

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000281

Gnomad NFE exome AF: 0.00326

Gnomad OTH exome AF: 0.00500

GnomAD4 exome AF: 0.00300 AC: 4377 AN: 1460674 Hom.: 14 Cov.: 29 AF XY: 0.00299 AC XY: 2172 AN XY: 726602

African (AFR) AF: 0.000629 AC: 21 AN: 33382

American (AMR) AF: 0.00534 AC: 238 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.00958 AC: 250 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86088

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53312

Middle Eastern (MID) AF: 0.0210 AC: 121 AN: 5760

European-Non Finnish (NFE) AF: 0.00298 AC: 3316 AN: 1111572

Other (OTH) AF: 0.00539 AC: 325 AN: 60294

GnomAD4 genome AF: 0.00287 AC: 437 AN: 152286 Hom.: 8 Cov.: 33 AF XY: 0.00261 AC XY: 194 AN XY: 74460

African (AFR) AF: 0.000698 AC: 29 AN: 41574

American (AMR) AF: 0.00484 AC: 74 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10614

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00307 AC: 209 AN: 68010

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00324 Hom.: 1

Bravo AF: 0.00386

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000541 AC: 2

ESP6500EA AF: 0.00354 AC: 29

ExAC AF: 0.00300 AC: 363

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00595

EpiControl AF: 0.00547

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	4	not provided (4)
-	-	2	Cardiomyopathy (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.79
Eigen	Benign	-0.017
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.76	T
PhyloP100		2.0
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.10
Sift	Benign	0.84	T
Polyphen		0.042	B
Vest4		0.22
MutPred		0.41		Gain of disorder (P = 0.0446)
MVP		0.27
MPC		0.094
ClinPred		0.015	T
GERP RS		4.8
Mutation Taster		=92/8	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: rs72648925; hg19: chr2-179600303;