rs16866425

Variant names:

• chr2-178633576-T-C
• rs16866425
• NM_001267550.2:c.42783A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178633576-T-C
• chr2-178633576-T-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.42783A>G​(p.Lys14261Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0438 in 1,613,282 control chromosomes in the GnomAD database, including 3,691 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (696 hom., cov: 32)
  • Exomes 𝑓: 0.041 (2995 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.743
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 2-178633576-T-C is Benign according to our data. Variant chr2-178633576-T-C is described in ClinVar as Benign. ClinVar VariationId is 46959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.743 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.149 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.42783A>G	p.Lys14261Lys	synonymous	Exon 232 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.37860A>G	p.Lys12620Lys	synonymous	Exon 182 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.35079A>G	p.Lys11693Lys	synonymous	Exon 181 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.42783A>G	p.Lys14261Lys	synonymous	Exon 232 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.42627A>G	p.Lys14209Lys	synonymous	Exon 230 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.42507A>G	p.Lys14169Lys	synonymous	Exon 230 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0731 AC: 11113 AN: 152032 Hom.: 687 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.0242

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.0584

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0575

GnomAD2 exomes AF: 0.0759 AC: 18819 AN: 248006 AF XY: 0.0732

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.0264

Gnomad EAS exome AF: 0.0272

Gnomad FIN exome AF: 0.0573

Gnomad NFE exome AF: 0.0241

Gnomad OTH exome AF: 0.0582

GnomAD4 exome AF: 0.0407 AC: 59482 AN: 1461132 Hom.: 2995 Cov.: 33 AF XY: 0.0429 AC XY: 31150 AN XY: 726848

African (AFR) AF: 0.143 AC: 4781 AN: 33446

American (AMR) AF: 0.191 AC: 8534 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0260 AC: 678 AN: 26120

East Asian (EAS) AF: 0.0132 AC: 524 AN: 39568

South Asian (SAS) AF: 0.156 AC: 13443 AN: 86250

European-Finnish (FIN) AF: 0.0585 AC: 3120 AN: 53360

Middle Eastern (MID) AF: 0.0397 AC: 229 AN: 5762

European-Non Finnish (NFE) AF: 0.0228 AC: 25317 AN: 1111598

Other (OTH) AF: 0.0473 AC: 2856 AN: 60332

GnomAD4 genome AF: 0.0733 AC: 11157 AN: 152150 Hom.: 696 Cov.: 32 AF XY: 0.0794 AC XY: 5903 AN XY: 74384

African (AFR) AF: 0.134 AC: 5547 AN: 41528

American (AMR) AF: 0.149 AC: 2268 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3470

East Asian (EAS) AF: 0.0245 AC: 126 AN: 5148

South Asian (SAS) AF: 0.159 AC: 765 AN: 4824

European-Finnish (FIN) AF: 0.0584 AC: 620 AN: 10620

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0231 AC: 1569 AN: 67978

Other (OTH) AF: 0.0569 AC: 120 AN: 2108

Alfa AF: 0.0455 Hom.: 289

Bravo AF: 0.0798

Asia WGS AF: 0.111 AC: 384 AN: 3476

EpiCase AF: 0.0213

EpiControl AF: 0.0207

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.2
DANN	Benign	0.68
PhyloP100		0.74
Mutation Taster		=73/27	polymorphism (auto)

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: rs16866425; hg19: chr2-179498303; COSMIC: COSV60092520; COSMIC: COSV60092520;