rs72648982

Variant names:

• chr2-178718126-T-C
• rs72648982
• NM_001267550.2:c.24880A>G

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.24880A>G​(p.Arg8294Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0274 in 1,611,002 control chromosomes in the GnomAD database, including 671 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (46 hom., cov: 33)
  • Exomes 𝑓: 0.028 (625 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 1.21
• Publications: 9 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=0.0025924444).
• BP6: Variant 2-178718126-T-C is Benign according to our data. Variant chr2-178718126-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46742.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 = 0.0206 (3133/152284) while in subpopulation NFE AF = 0.0298 (2026/68008). AF 95% confidence interval is 0.0287. There are 46 homozygotes in GnomAd4. There are 1461 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 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.24880A>G	p.Arg8294Gly	missense	Exon 86 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.23929A>G	p.Arg7977Gly	missense	Exon 84 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.21148A>G	p.Arg7050Gly	missense	Exon 83 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.24880A>G	p.Arg8294Gly	missense	Exon 86 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.24880A>G	p.Arg8294Gly	missense	Exon 86 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.24604A>G	p.Arg8202Gly	missense	Exon 84 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3135 AN: 152166 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.00543

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0315

GnomAD2 exomes AF: 0.0222 AC: 5464 AN: 246622 AF XY: 0.0230

Gnomad AFR exome AF: 0.00524

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0515

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.0302

Gnomad OTH exome AF: 0.0283

GnomAD4 exome AF: 0.0281 AC: 40930 AN: 1458718 Hom.: 625 Cov.: 35 AF XY: 0.0279 AC XY: 20268 AN XY: 725824

African (AFR) AF: 0.00547 AC: 183 AN: 33460

American (AMR) AF: 0.0127 AC: 569 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0546 AC: 1426 AN: 26124

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39692

South Asian (SAS) AF: 0.0189 AC: 1631 AN: 86248

European-Finnish (FIN) AF: 0.0197 AC: 999 AN: 50702

Middle Eastern (MID) AF: 0.0524 AC: 302 AN: 5762

European-Non Finnish (NFE) AF: 0.0306 AC: 34039 AN: 1111678

Other (OTH) AF: 0.0295 AC: 1777 AN: 60338

GnomAD4 genome AF: 0.0206 AC: 3133 AN: 152284 Hom.: 46 Cov.: 33 AF XY: 0.0196 AC XY: 1461 AN XY: 74456

African (AFR) AF: 0.00541 AC: 225 AN: 41560

American (AMR) AF: 0.0214 AC: 328 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0507 AC: 176 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4828

European-Finnish (FIN) AF: 0.0167 AC: 177 AN: 10624

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0298 AC: 2026 AN: 68008

Other (OTH) AF: 0.0312 AC: 66 AN: 2116

Alfa AF: 0.0269 Hom.: 189

Bravo AF: 0.0205

TwinsUK AF: 0.0329 AC: 122

ALSPAC AF: 0.0340 AC: 131

ESP6500AA AF: 0.00566 AC: 21

ESP6500EA AF: 0.0308 AC: 253

ExAC AF: 0.0210 AC: 2536

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.0336

EpiControl AF: 0.0332

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	4	not provided (4)
-	-	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	Benign	0.22
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.89
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.097
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.76	T
PhyloP100		1.2
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.18
Sift	Benign	0.075	T
Polyphen		0.15	B
Vest4		0.17
MPC		0.12
ClinPred		0.025	T
GERP RS		5.0
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs72648982; hg19: chr2-179582853; COSMIC: COSV60066314; COSMIC: COSV60066314;