rs2303832

Variant names:

• chr2-178607565-T-A
• rs2303832
• NM_001267550.2:c.53123A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178607565-T-A
• chr2-178607565-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.53123A>T​(p.Lys17708Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,613,156 control chromosomes in the GnomAD database, including 634 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict 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. K17708V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.021 (63 hom., cov: 32)
  • Exomes 𝑓: 0.024 (571 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 1.88
• Publications: 18 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=0.0014025569).
• BP6: Variant 2-178607565-T-A is Benign according to our data. Variant chr2-178607565-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0875 is higher than 0.05.

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.53123A>T	p.Lys17708Ile	missense	Exon 277 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.48200A>T	p.Lys16067Ile	missense	Exon 227 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.45419A>T	p.Lys15140Ile	missense	Exon 226 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.53123A>T	p.Lys17708Ile	missense	Exon 277 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.52967A>T	p.Lys17656Ile	missense	Exon 275 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.52847A>T	p.Lys17616Ile	missense	Exon 275 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3245 AN: 151926 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.00461

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.0943

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.0448

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.0291 AC: 7219 AN: 248006 AF XY: 0.0273

Gnomad AFR exome AF: 0.00505

Gnomad AMR exome AF: 0.0338

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.103

Gnomad FIN exome AF: 0.0475

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0275

GnomAD4 exome AF: 0.0238 AC: 34757 AN: 1461112 Hom.: 571 Cov.: 32 AF XY: 0.0233 AC XY: 16935 AN XY: 726860

African (AFR) AF: 0.00416 AC: 139 AN: 33428

American (AMR) AF: 0.0321 AC: 1437 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 374 AN: 26124

East Asian (EAS) AF: 0.0920 AC: 3652 AN: 39676

South Asian (SAS) AF: 0.00715 AC: 617 AN: 86242

European-Finnish (FIN) AF: 0.0490 AC: 2615 AN: 53380

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5758

European-Non Finnish (NFE) AF: 0.0220 AC: 24443 AN: 1111460

Other (OTH) AF: 0.0236 AC: 1421 AN: 60330

GnomAD4 genome AF: 0.0213 AC: 3242 AN: 152044 Hom.: 63 Cov.: 32 AF XY: 0.0218 AC XY: 1620 AN XY: 74306

African (AFR) AF: 0.00460 AC: 191 AN: 41538

American (AMR) AF: 0.0231 AC: 353 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3472

East Asian (EAS) AF: 0.0945 AC: 483 AN: 5112

South Asian (SAS) AF: 0.00746 AC: 36 AN: 4826

European-Finnish (FIN) AF: 0.0448 AC: 476 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0230 AC: 1562 AN: 67910

Other (OTH) AF: 0.0213 AC: 45 AN: 2112

Alfa AF: 0.0227 Hom.: 51

Bravo AF: 0.0198

TwinsUK AF: 0.0254 AC: 94

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00531 AC: 20

ESP6500EA AF: 0.0204 AC: 168

ExAC AF: 0.0291 AC: 3516

Asia WGS AF: 0.0360 AC: 124 AN: 3478

EpiCase AF: 0.0199

EpiControl AF: 0.0215

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	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	not provided (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	0.12
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.89
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.9
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.14
Sift	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.15
ClinPred		0.021	T
GERP RS		0.53
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2303832; hg19: chr2-179472292; COSMIC: COSV99045729; COSMIC: COSV99045729;