NM_001267550.2:c.62149A>G

Variant names:

• chr2-178589576-T-C
• rs75458912
• NM_001267550.2:c.62149A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001267550.2(TTN):​c.62149A>G​(p.Arg20717Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000104 in 1,613,438 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R20717R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 5.07
• Publications: 4 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014564544).
• BP6: Variant 2-178589576-T-C is Benign according to our data. Variant chr2-178589576-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 467346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000105 (153/1461208) while in subpopulation EAS AF = 0.00359 (142/39606). AF 95% confidence interval is 0.0031. There are 1 homozygotes in GnomAdExome4. There are 74 alleles in the male GnomAdExome4 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.62149A>G	p.Arg20717Gly	missense	Exon 304 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.57226A>G	p.Arg19076Gly	missense	Exon 254 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.54445A>G	p.Arg18149Gly	missense	Exon 253 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.62149A>G	p.Arg20717Gly	missense	Exon 304 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.61993A>G	p.Arg20665Gly	missense	Exon 302 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.61873A>G	p.Arg20625Gly	missense	Exon 302 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000266 AC: 66 AN: 247740 AF XY: 0.000223

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00353

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1461208 Hom.: 1 Cov.: 33 AF XY: 0.000102 AC XY: 74 AN XY: 726882

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.0000447 AC: 2 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00359 AC: 142 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111632

Other (OTH) AF: 0.0000497 AC: 3 AN: 60358

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74430

African (AFR) AF: 0.0000240 AC: 1 AN: 41580

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

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

East Asian (EAS) AF: 0.00233 AC: 12 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000613 Hom.: 0

Bravo AF: 0.000166

ExAC AF: 0.000224 AC: 27

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (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	Cardiomyopathy (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	not specified (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.89
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.019	D
Polyphen		0.98	D
Vest4		0.50
MVP		0.47
MPC		0.37
ClinPred		0.096	T
GERP RS		6.2
Mutation Taster		=65/35	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: rs75458912; hg19: chr2-179454303;