rs72648951

Variant names:

• chr2-178729034-T-C
• rs72648951
• NM_001267550.2:c.19004A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178729034-T-C
• chr2-178729034-T-A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.19004A>G​(p.Asp6335Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00166 in 1,612,910 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts 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. D6335N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0094 (20 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (22 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 3.95
• 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 -16 ACMG points.

• BP6: Variant 2-178729034-T-C is Benign according to our data. Variant chr2-178729034-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46651.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 = 0.00936 (1425/152232) while in subpopulation AFR AF = 0.0323 (1342/41556). AF 95% confidence interval is 0.0309. There are 20 homozygotes in GnomAd4. There are 647 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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.19004A>G	p.Asp6335Gly	missense	Exon 65 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.18053A>G	p.Asp6018Gly	missense	Exon 63 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.15272A>G	p.Asp5091Gly	missense	Exon 62 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.19004A>G	p.Asp6335Gly	missense	Exon 65 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.19004A>G	p.Asp6335Gly	missense	Exon 65 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.18728A>G	p.Asp6243Gly	missense	Exon 63 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00937 AC: 1426 AN: 152114 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00228 AC: 563 AN: 246512 AF XY: 0.00160

Gnomad AFR exome AF: 0.0326

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000719

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.000863 AC: 1260 AN: 1460678 Hom.: 22 Cov.: 32 AF XY: 0.000723 AC XY: 525 AN XY: 726586

African (AFR) AF: 0.0305 AC: 1020 AN: 33448

American (AMR) AF: 0.00168 AC: 75 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111438

Other (OTH) AF: 0.00214 AC: 129 AN: 60312

GnomAD4 genome AF: 0.00936 AC: 1425 AN: 152232 Hom.: 20 Cov.: 33 AF XY: 0.00869 AC XY: 647 AN XY: 74428

African (AFR) AF: 0.0323 AC: 1342 AN: 41556

American (AMR) AF: 0.00353 AC: 54 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67990

Other (OTH) AF: 0.0109 AC: 23 AN: 2116

Alfa AF: 0.00301 Hom.: 20

Bravo AF: 0.0106

ESP6500AA AF: 0.0280 AC: 104

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00292 AC: 353

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.0000596

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	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	Cardiomyopathy (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.94
Eigen	Benign	-0.063
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.9
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.10
Sift	Benign	0.63	T
Polyphen		0.0010	B
Vest4		0.42
MVP		0.11
MPC		0.11
ClinPred		0.013	T
GERP RS		4.8
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72648951; hg19: chr2-179593761; COSMIC: COSV99045627; COSMIC: COSV99045627;