chr2-178735535-A-C

Variant names:

• chr2-178735535-A-C
• rs537312655
• NM_001267550.2:c.14911T>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001267550.2(TTN):​c.14911T>G​(p.Cys4971Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,594,258 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000085 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 2.25
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01079309).
• BP6: Variant 2-178735535-A-C is Benign according to our data. Variant chr2-178735535-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203242.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000414 (63/152200) while in subpopulation AMR AF = 0.00399 (61/15272). AF 95% confidence interval is 0.00319. There are 1 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.14911T>G	p.Cys4971Gly	missense	Exon 50 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.13960T>G	p.Cys4654Gly	missense	Exon 48 of 313	NP_001243779.1
	TTN	NM_133378.4		c.11179T>G	p.Cys3727Gly	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.14911T>G	p.Cys4971Gly	missense	Exon 50 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.14911T>G	p.Cys4971Gly	missense	Exon 50 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.14635T>G	p.Cys4879Gly	missense	Exon 48 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152200 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000439 AC: 102 AN: 232510 AF XY: 0.000326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00268

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000280

Gnomad OTH exome AF: 0.00253

GnomAD4 exome AF: 0.0000853 AC: 123 AN: 1442058 Hom.: 1 Cov.: 29 AF XY: 0.0000685 AC XY: 49 AN XY: 715666

African (AFR) AF: 0.00 AC: 0 AN: 32302

American (AMR) AF: 0.00245 AC: 102 AN: 41566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39452

South Asian (SAS) AF: 0.00 AC: 0 AN: 81824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 0.0000109 AC: 12 AN: 1104018

Other (OTH) AF: 0.000151 AC: 9 AN: 59426

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152200 Hom.: 1 Cov.: 33 AF XY: 0.000484 AC XY: 36 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00399 AC: 61 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.000468

ExAC AF: 0.000422 AC: 51

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.71
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.74	T
PhyloP100		2.2
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.12
Sift	Benign	0.095	T
Polyphen		0.012	B
Vest4		0.22
MutPred		0.43		Loss of stability (P = 0.0209)
MVP		0.51
MPC		0.11
ClinPred		0.037	T
GERP RS		1.9
Mutation Taster		=90/10	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: rs537312655; hg19: chr2-179600262; COSMIC: COSV104641993;