rs72646843

Variant names:

• chr2-178591235-C-G
• rs72646843
• NM_001267550.2:c.60490G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178591235-C-G
• chr2-178591235-C-T

Variant summary

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

The NM_001267550.2(TTN):​c.60490G>C​(p.Val20164Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000714 in 1,613,302 control chromosomes in the GnomAD database, including 10 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. V20164E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (3 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 1.48
• Publications: 7 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=0.0050988197).
• BP6: Variant 2-178591235-C-G is Benign according to our data. Variant chr2-178591235-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00377 (573/152134) while in subpopulation AFR AF = 0.013 (540/41536). AF 95% confidence interval is 0.0121. There are 7 homozygotes in GnomAd4. There are 264 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.60490G>C	p.Val20164Leu	missense	Exon 304 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.55567G>C	p.Val18523Leu	missense	Exon 254 of 313	NP_001243779.1
	TTN	NM_133378.4		c.52786G>C	p.Val17596Leu	missense	Exon 253 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.60490G>C	p.Val20164Leu	missense	Exon 304 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.60334G>C	p.Val20112Leu	missense	Exon 302 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.60214G>C	p.Val20072Leu	missense	Exon 302 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 571 AN: 152016 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000982 AC: 244 AN: 248408 AF XY: 0.000801

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000396 AC: 579 AN: 1461168 Hom.: 3 Cov.: 35 AF XY: 0.000369 AC XY: 268 AN XY: 726864

African (AFR) AF: 0.0142 AC: 475 AN: 33440

American (AMR) AF: 0.000693 AC: 31 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5756

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111556

Other (OTH) AF: 0.000712 AC: 43 AN: 60352

GnomAD4 genome AF: 0.00377 AC: 573 AN: 152134 Hom.: 7 Cov.: 32 AF XY: 0.00355 AC XY: 264 AN XY: 74350

African (AFR) AF: 0.0130 AC: 540 AN: 41536

American (AMR) AF: 0.00151 AC: 23 AN: 15262

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67980

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.000191 Hom.: 0

Bravo AF: 0.00420

ESP6500AA AF: 0.0138 AC: 53

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00132 AC: 159

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Primary dilated cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Benign	0.62
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.61	N
PhyloP100		1.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.15
Sift	Benign	0.42	T
Polyphen		0.0020	B
Vest4		0.12
MutPred		0.56		Loss of phosphorylation at T18526 (P = 0.1716)
MVP		0.51
MPC		0.083
ClinPred		0.0090	T
GERP RS		6.1
Mutation Taster		=100/0	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: rs72646843; hg19: chr2-179455962; COSMIC: COSV99045518;