rs62621236

Variant names:

• chr2-178543986-A-G
• rs62621236
• NM_001267550.2:c.96158T>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.96158T>C​(p.Ile32053Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0545 in 1,613,566 control chromosomes in the GnomAD database, including 4,636 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I32053M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.084 (860 hom., cov: 33)
  • Exomes 𝑓: 0.051 (3776 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 6.29
• Publications: 16 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=0.0017148554).
• BP6: Variant 2-178543986-A-G is Benign according to our data. Variant chr2-178543986-A-G is described in ClinVar as Benign. ClinVar VariationId is 47566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.167 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.96158T>C	p.Ile32053Thr	missense	Exon 346 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.91235T>C	p.Ile30412Thr	missense	Exon 296 of 313	NP_001243779.1
	TTN	NM_133378.4		c.88454T>C	p.Ile29485Thr	missense	Exon 295 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.96158T>C	p.Ile32053Thr	missense	Exon 346 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.96002T>C	p.Ile32001Thr	missense	Exon 344 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.95882T>C	p.Ile31961Thr	missense	Exon 344 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0833 AC: 12657 AN: 151994 Hom.: 845 Cov.: 33

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.0249

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0584

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0331

Gnomad OTH AF: 0.0712

GnomAD2 exomes AF: 0.0852 AC: 21216 AN: 248908 AF XY: 0.0826

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.0298

Gnomad EAS exome AF: 0.0275

Gnomad FIN exome AF: 0.0577

Gnomad NFE exome AF: 0.0347

Gnomad OTH exome AF: 0.0665

GnomAD4 exome AF: 0.0515 AC: 75229 AN: 1461454 Hom.: 3776 Cov.: 33 AF XY: 0.0538 AC XY: 39134 AN XY: 727012

African (AFR) AF: 0.151 AC: 5052 AN: 33454

American (AMR) AF: 0.200 AC: 8941 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0293 AC: 766 AN: 26126

East Asian (EAS) AF: 0.0138 AC: 547 AN: 39696

South Asian (SAS) AF: 0.175 AC: 15095 AN: 86254

European-Finnish (FIN) AF: 0.0592 AC: 3162 AN: 53384

Middle Eastern (MID) AF: 0.0538 AC: 310 AN: 5762

European-Non Finnish (NFE) AF: 0.0340 AC: 37758 AN: 1111706

Other (OTH) AF: 0.0596 AC: 3598 AN: 60356

GnomAD4 genome AF: 0.0836 AC: 12717 AN: 152112 Hom.: 860 Cov.: 33 AF XY: 0.0893 AC XY: 6644 AN XY: 74360

African (AFR) AF: 0.145 AC: 6014 AN: 41478

American (AMR) AF: 0.166 AC: 2534 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3470

East Asian (EAS) AF: 0.0252 AC: 130 AN: 5164

South Asian (SAS) AF: 0.177 AC: 853 AN: 4820

European-Finnish (FIN) AF: 0.0584 AC: 619 AN: 10606

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0330 AC: 2247 AN: 67988

Other (OTH) AF: 0.0705 AC: 149 AN: 2114

Alfa AF: 0.0480 Hom.: 712

Bravo AF: 0.0907

TwinsUK AF: 0.0316 AC: 117

ALSPAC AF: 0.0304 AC: 117

ESP6500AA AF: 0.154 AC: 609

ESP6500EA AF: 0.0322 AC: 268

ExAC AF: 0.0808 AC: 9762

Asia WGS AF: 0.122 AC: 424 AN: 3478

EpiCase AF: 0.0326

EpiControl AF: 0.0337

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.89
Eigen	Benign	-0.090
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.17	N
PhyloP100		6.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.22
Sift	Benign	0.15	T
Polyphen		0.028	B
Vest4		0.33
MPC		0.11
ClinPred		0.017	T
GERP RS		5.7
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: rs62621236; hg19: chr2-179408713; COSMIC: COSV60092282; COSMIC: COSV60092282;