rs201562505

Variant names:

• chr2-178565431-T-C
• rs201562505
• NM_001267550.2:c.80701A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178565431-T-C
• chr2-178565431-T-G

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.80701A>G​(p.Ile26901Val) variant causes a missense change. The variant allele was found at a frequency of 0.000927 in 1,613,444 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00099 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00092 (10 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:18 O:1
• Conservation: PhyloP100: 4.92
• Publications: 8 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=0.0044291914).
• BP6: Variant 2-178565431-T-C is Benign according to our data. Variant chr2-178565431-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 165813.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00092 (1344/1461246) while in subpopulation MID AF = 0.00538 (31/5758). AF 95% confidence interval is 0.0039. There are 10 homozygotes in GnomAdExome4. There are 694 alleles in the male GnomAdExome4 subpopulation. Median coverage is 37. 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.80701A>G	p.Ile26901Val	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.75778A>G	p.Ile25260Val	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.72997A>G	p.Ile24333Val	missense	Exon 275 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.80701A>G	p.Ile26901Val	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.80545A>G	p.Ile26849Val	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.80425A>G	p.Ile26809Val	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000993 AC: 151 AN: 152080 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00162 AC: 403 AN: 248414 AF XY: 0.00165

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.0315

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000498

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.000920 AC: 1344 AN: 1461246 Hom.: 10 Cov.: 37 AF XY: 0.000955 AC XY: 694 AN XY: 726928

African (AFR) AF: 0.000209 AC: 7 AN: 33436

American (AMR) AF: 0.000447 AC: 20 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0338 AC: 883 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00538 AC: 31 AN: 5758

European-Non Finnish (NFE) AF: 0.000210 AC: 234 AN: 1111646

Other (OTH) AF: 0.00267 AC: 161 AN: 60336

GnomAD4 genome AF: 0.000992 AC: 151 AN: 152198 Hom.: 2 Cov.: 33 AF XY: 0.000981 AC XY: 73 AN XY: 74418

African (AFR) AF: 0.0000241 AC: 1 AN: 41550

American (AMR) AF: 0.00190 AC: 29 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3470

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

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: 0.000294 AC: 20 AN: 67992

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00162 Hom.: 5

Bravo AF: 0.00114

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00135 AC: 11

ExAC AF: 0.00136 AC: 164

EpiCase AF: 0.000928

EpiControl AF: 0.00142

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	7	not specified (9)
-	-	4	not provided (4)
-	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	Primary dilated cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Benign	0.89
Eigen	Benign	-0.11
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.15	N
PhyloP100		4.9
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.11
Sift	Benign	0.24	T
Polyphen		0.020	B
Vest4		0.076
MVP		0.28
MPC		0.078
ClinPred		0.016	T
GERP RS		5.5
Mutation Taster		=81/19	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: rs201562505; hg19: chr2-179430158; COSMIC: COSV60190873;