rs56307213

Variant names:

• chr2-178566349-C-G
• rs56307213
• NM_001267550.2:c.79783G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.79783G>C​(p.Asp26595His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,613,520 control chromosomes in the GnomAD database, including 304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D26595D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (22 hom., cov: 33)
  • Exomes 𝑓: 0.018 (282 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:28
• Conservation: PhyloP100: 7.86
• Publications: 13 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=0.008546919).
• BP6: Variant 2-178566349-C-G is Benign according to our data. Variant chr2-178566349-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0144 (2195/152162) while in subpopulation NFE AF = 0.0213 (1449/67982). AF 95% confidence interval is 0.0204. There are 22 homozygotes in GnomAd4. There are 1060 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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.79783G>C	p.Asp26595His	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.74860G>C	p.Asp24954His	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.72079G>C	p.Asp24027His	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.79783G>C	p.Asp26595His	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.79627G>C	p.Asp26543His	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.79507G>C	p.Asp26503His	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2197 AN: 152044 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.00418

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.0216

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0146 AC: 3638 AN: 248720 AF XY: 0.0148

Gnomad AFR exome AF: 0.00349

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.00865

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0222

Gnomad NFE exome AF: 0.0198

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0179 AC: 26133 AN: 1461358 Hom.: 282 Cov.: 38 AF XY: 0.0178 AC XY: 12933 AN XY: 726970

African (AFR) AF: 0.00311 AC: 104 AN: 33460

American (AMR) AF: 0.0110 AC: 492 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00907 AC: 237 AN: 26124

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39686

South Asian (SAS) AF: 0.0111 AC: 957 AN: 86254

European-Finnish (FIN) AF: 0.0240 AC: 1281 AN: 53310

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5764

European-Non Finnish (NFE) AF: 0.0198 AC: 22014 AN: 1111688

Other (OTH) AF: 0.0162 AC: 978 AN: 60356

GnomAD4 genome AF: 0.0144 AC: 2195 AN: 152162 Hom.: 22 Cov.: 33 AF XY: 0.0143 AC XY: 1060 AN XY: 74366

African (AFR) AF: 0.00416 AC: 173 AN: 41552

American (AMR) AF: 0.0146 AC: 222 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3472

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5152

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4820

European-Finnish (FIN) AF: 0.0216 AC: 229 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0213 AC: 1449 AN: 67982

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0171 Hom.: 26

Bravo AF: 0.0128

TwinsUK AF: 0.0167 AC: 62

ALSPAC AF: 0.0187 AC: 72

ESP6500AA AF: 0.00469 AC: 19

ESP6500EA AF: 0.0200 AC: 168

ExAC AF: 0.0147 AC: 1784

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0205

EpiControl AF: 0.0211

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	4	not provided (4)
-	-	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	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Benign	0.87
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0085	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.34
MPC		0.50
ClinPred		0.046	T
GERP RS		5.9
Mutation Taster		=95/5	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: rs56307213; hg19: chr2-179431076;