NM_001267550.2:c.20602G>A

Variant names:

• chr2-178725602-C-T
• rs17355460
• NM_001267550.2:c.20602G>A

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.20602G>A​(p.Gly6868Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0158 in 1,608,306 control chromosomes in the GnomAD database, including 239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (21 hom., cov: 33)
  • Exomes 𝑓: 0.016 (218 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 5.85
• Publications: 14 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]

ENSG00000267784 (HGNC:):

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=0.007750064).
• BP6: Variant 2-178725602-C-T is Benign according to our data. Variant chr2-178725602-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0116 (1767/152168) while in subpopulation NFE AF = 0.0177 (1204/67990). AF 95% confidence interval is 0.0169. There are 21 homozygotes in GnomAd4. There are 805 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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.20602G>A	p.Gly6868Arg	missense	Exon 71 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.19651G>A	p.Gly6551Arg	missense	Exon 69 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.16870G>A	p.Gly5624Arg	missense	Exon 68 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.20602G>A	p.Gly6868Arg	missense	Exon 71 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.20602G>A	p.Gly6868Arg	missense	Exon 71 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.20326G>A	p.Gly6776Arg	missense	Exon 69 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1769 AN: 152050 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00810

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0118 AC: 2870 AN: 243616 AF XY: 0.0121

Gnomad AFR exome AF: 0.00273

Gnomad AMR exome AF: 0.00522

Gnomad ASJ exome AF: 0.00890

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0158

GnomAD4 exome AF: 0.0162 AC: 23591 AN: 1456138 Hom.: 218 Cov.: 31 AF XY: 0.0160 AC XY: 11547 AN XY: 723872

African (AFR) AF: 0.00256 AC: 85 AN: 33262

American (AMR) AF: 0.00668 AC: 296 AN: 44292

Ashkenazi Jewish (ASJ) AF: 0.00943 AC: 243 AN: 25764

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39608

South Asian (SAS) AF: 0.00787 AC: 670 AN: 85118

European-Finnish (FIN) AF: 0.0133 AC: 705 AN: 53172

Middle Eastern (MID) AF: 0.0124 AC: 71 AN: 5726

European-Non Finnish (NFE) AF: 0.0185 AC: 20571 AN: 1109102

Other (OTH) AF: 0.0158 AC: 948 AN: 60094

GnomAD4 genome AF: 0.0116 AC: 1767 AN: 152168 Hom.: 21 Cov.: 33 AF XY: 0.0108 AC XY: 805 AN XY: 74392

African (AFR) AF: 0.00325 AC: 135 AN: 41552

American (AMR) AF: 0.0109 AC: 167 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00790 AC: 38 AN: 4810

European-Finnish (FIN) AF: 0.0105 AC: 111 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0177 AC: 1204 AN: 67990

Other (OTH) AF: 0.0171 AC: 36 AN: 2110

Alfa AF: 0.0154 Hom.: 71

Bravo AF: 0.0118

TwinsUK AF: 0.0210 AC: 78

ALSPAC AF: 0.0228 AC: 88

ESP6500AA AF: 0.00349 AC: 13

ESP6500EA AF: 0.0173 AC: 142

ExAC AF: 0.0112 AC: 1355

Asia WGS AF: 0.00462 AC: 16 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	5	not provided (5)
-	-	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	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Benign	0.85
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0078	T
MetaSVM	Uncertain	0.56	D
PhyloP100		5.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.60
Sift	Benign	0.085	T
Polyphen		1.0	D
Vest4		0.18
MutPred		0.78		Loss of catalytic residue at A6550 (P = 0.0402)
MPC		0.50
ClinPred		0.038	T
GERP RS		5.9
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs17355460; hg19: chr2-179590329; COSMIC: COSV60066329;