rs56310931

Variant names:

• chr2-178559831-C-T
• rs56310931
• NM_001267550.2:c.86301G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.86301G>A​(p.Lys28767Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00972 in 1,610,716 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0099 (102 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 0.642
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 2-178559831-C-T is Benign according to our data. Variant chr2-178559831-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.642 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00787 (1197/152184) while in subpopulation NFE AF = 0.0106 (723/68014). AF 95% confidence interval is 0.00999. There are 7 homozygotes in GnomAd4. There are 593 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.86301G>A	p.Lys28767Lys	synonymous	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.81378G>A	p.Lys27126Lys	synonymous	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.78597G>A	p.Lys26199Lys	synonymous	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.86301G>A	p.Lys28767Lys	synonymous	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.86145G>A	p.Lys28715Lys	synonymous	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.86025G>A	p.Lys28675Lys	synonymous	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00787 AC: 1196 AN: 152066 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00196

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00446

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00685

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00876 AC: 2161 AN: 246564 AF XY: 0.00878

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.00427

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.0120

GnomAD4 exome AF: 0.00991 AC: 14455 AN: 1458532 Hom.: 102 Cov.: 32 AF XY: 0.00984 AC XY: 7141 AN XY: 725618

African (AFR) AF: 0.00123 AC: 41 AN: 33462

American (AMR) AF: 0.00439 AC: 196 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 419 AN: 26094

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00667 AC: 575 AN: 86156

European-Finnish (FIN) AF: 0.0154 AC: 780 AN: 50750

Middle Eastern (MID) AF: 0.00365 AC: 21 AN: 5760

European-Non Finnish (NFE) AF: 0.0106 AC: 11834 AN: 1111606

Other (OTH) AF: 0.00975 AC: 588 AN: 60336

GnomAD4 genome AF: 0.00787 AC: 1197 AN: 152184 Hom.: 7 Cov.: 33 AF XY: 0.00797 AC XY: 593 AN XY: 74392

African (AFR) AF: 0.00195 AC: 81 AN: 41528

American (AMR) AF: 0.00452 AC: 69 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00686 AC: 33 AN: 4814

European-Finnish (FIN) AF: 0.0188 AC: 199 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0106 AC: 723 AN: 68014

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00952 Hom.: 7

Bravo AF: 0.00670

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0110

EpiControl AF: 0.00972

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	not provided (5)
-	-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.34
DANN	Benign	0.68
PhyloP100		0.64
Mutation Taster		=83/17	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: rs56310931; hg19: chr2-179424558;