rs72648990

Variant names:

• chr2-178714130-G-A
• rs72648990
• NM_001267550.2:c.26528C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178714130-G-A
• chr2-178714130-G-C

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.26528C>T​(p.Thr8843Met) variant causes a missense change. The variant allele was found at a frequency of 0.000381 in 1,613,490 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. T8843K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:6
• Conservation: PhyloP100: 6.58
• Publications: 6 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.065653354).
• BP6: Variant 2-178714130-G-A is Benign according to our data. Variant chr2-178714130-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46782.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000388 (567/1461286) while in subpopulation MID AF = 0.00295 (17/5762). AF 95% confidence interval is 0.00188. There are 2 homozygotes in GnomAdExome4. There are 286 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.26528C>T	p.Thr8843Met	missense	Exon 92 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.25577C>T	p.Thr8526Met	missense	Exon 90 of 313	NP_001243779.1
	TTN	NM_133378.4		c.22796C>T	p.Thr7599Met	missense	Exon 89 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.26528C>T	p.Thr8843Met	missense	Exon 92 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.26528C>T	p.Thr8843Met	missense	Exon 92 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.26252C>T	p.Thr8751Met	missense	Exon 90 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152086 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.000402 AC: 100 AN: 248552 AF XY: 0.000378

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000435

Gnomad OTH exome AF: 0.000831

GnomAD4 exome AF: 0.000388 AC: 567 AN: 1461286 Hom.: 2 Cov.: 34 AF XY: 0.000393 AC XY: 286 AN XY: 726900

African (AFR) AF: 0.000239 AC: 8 AN: 33438

American (AMR) AF: 0.00103 AC: 46 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86178

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53390

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5762

European-Non Finnish (NFE) AF: 0.000376 AC: 418 AN: 1111672

Other (OTH) AF: 0.000646 AC: 39 AN: 60352

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74410

African (AFR) AF: 0.000120 AC: 5 AN: 41538

American (AMR) AF: 0.000523 AC: 8 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68006

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.000409 Hom.: 0

Bravo AF: 0.000472

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000856 AC: 7

ExAC AF: 0.000348 AC: 42

EpiCase AF: 0.000764

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	not provided (6)
-	1	2	not specified (3)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy (1)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Hypertrophic cardiomyopathy (1)
-	1	-	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.90
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
PhyloP100		6.6
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.14
Sift	Benign	0.085	T
Polyphen		0.029	B
Vest4		0.19
MVP		0.30
MPC		0.089
ClinPred		0.047	T
GERP RS		5.9
Mutation Taster		=88/12	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: rs72648990; hg19: chr2-179578857; COSMIC: COSV100597464; COSMIC: COSV100597464;