rs72648949

Variant names:

• chr2-178729380-G-C
• rs72648949
• NM_001267550.2:c.18776C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178729380-G-C
• chr2-178729380-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.18776C>G​(p.Thr6259Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,613,572 control chromosomes in the GnomAD database, including 17 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T6259A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (15 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:22
• Conservation: PhyloP100: 1.61
• 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]

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057101846).
• BP6: Variant 2-178729380-G-C is Benign according to our data. Variant chr2-178729380-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46644.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00262 (399/152194) while in subpopulation AMR AF = 0.00392 (60/15290). AF 95% confidence interval is 0.00313. There are 2 homozygotes in GnomAd4. There are 179 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.18776C>G	p.Thr6259Ser	missense	Exon 64 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.17825C>G	p.Thr5942Ser	missense	Exon 62 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.15044C>G	p.Thr5015Ser	missense	Exon 61 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.18776C>G	p.Thr6259Ser	missense	Exon 64 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.18776C>G	p.Thr6259Ser	missense	Exon 64 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.18500C>G	p.Thr6167Ser	missense	Exon 62 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 399 AN: 152076 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00324 AC: 804 AN: 247936 AF XY: 0.00326

Gnomad AFR exome AF: 0.000648

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.0321

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.00448

GnomAD4 exome AF: 0.00276 AC: 4032 AN: 1461378 Hom.: 15 Cov.: 33 AF XY: 0.00283 AC XY: 2058 AN XY: 726972

African (AFR) AF: 0.000987 AC: 33 AN: 33448

American (AMR) AF: 0.00141 AC: 63 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0344 AC: 898 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00130 AC: 112 AN: 86256

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53392

Middle Eastern (MID) AF: 0.0129 AC: 74 AN: 5758

European-Non Finnish (NFE) AF: 0.00230 AC: 2552 AN: 1111658

Other (OTH) AF: 0.00466 AC: 281 AN: 60360

GnomAD4 genome AF: 0.00262 AC: 399 AN: 152194 Hom.: 2 Cov.: 33 AF XY: 0.00241 AC XY: 179 AN XY: 74404

African (AFR) AF: 0.000313 AC: 13 AN: 41538

American (AMR) AF: 0.00392 AC: 60 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 96 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00297 AC: 202 AN: 67994

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00476 Hom.: 3

Bravo AF: 0.00270

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00495 AC: 41

ExAC AF: 0.00299 AC: 361

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	5	not provided (5)
-	-	1	Atrial fibrillation;C0007193:Primary dilated cardiomyopathy;C0349788:Arrhythmogenic right ventricular cardiomyopathy (1)
-	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	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.78
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.6
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.065
Sift	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.41		Gain of disorder (P = 0.0692)
MVP		0.14
MPC		0.075
ClinPred		0.0050	T
GERP RS		3.0
Mutation Taster		=95/5	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: rs72648949; hg19: chr2-179594107; COSMIC: COSV60063050; COSMIC: COSV60063050;