rs62621206

Variant names:

• chr2-178545555-A-G
• rs62621206
• NM_001267550.2:c.95555T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178545555-A-G
• chr2-178545555-A-C
• chr2-178545555-A-T

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.95555T>C​(p.Leu31852Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0151 in 1,613,736 control chromosomes in the GnomAD database, including 227 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L31852L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (20 hom., cov: 33)
  • Exomes 𝑓: 0.016 (207 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 3.59
• 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=0.00678429).
• BP6: Variant 2-178545555-A-G is Benign according to our data. Variant chr2-178545555-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47559.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 = 0.0112 (1704/152256) while in subpopulation NFE AF = 0.0173 (1174/68014). AF 95% confidence interval is 0.0164. There are 20 homozygotes in GnomAd4. There are 772 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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.95555T>C	p.Leu31852Pro	missense	Exon 344 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.90632T>C	p.Leu30211Pro	missense	Exon 294 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.87851T>C	p.Leu29284Pro	missense	Exon 293 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.95555T>C	p.Leu31852Pro	missense	Exon 344 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.95399T>C	p.Leu31800Pro	missense	Exon 342 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.95279T>C	p.Leu31760Pro	missense	Exon 342 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1706 AN: 152138 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0109 AC: 2720 AN: 249012 AF XY: 0.0111

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00539

Gnomad ASJ exome AF: 0.00875

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.0174

Gnomad OTH exome AF: 0.0154

GnomAD4 exome AF: 0.0155 AC: 22675 AN: 1461480 Hom.: 207 Cov.: 32 AF XY: 0.0151 AC XY: 10978 AN XY: 727018

African (AFR) AF: 0.00251 AC: 84 AN: 33466

American (AMR) AF: 0.00702 AC: 314 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00934 AC: 244 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.00285 AC: 246 AN: 86256

European-Finnish (FIN) AF: 0.0130 AC: 696 AN: 53402

Middle Eastern (MID) AF: 0.0144 AC: 83 AN: 5762

European-Non Finnish (NFE) AF: 0.0180 AC: 20065 AN: 1111698

Other (OTH) AF: 0.0156 AC: 941 AN: 60360

GnomAD4 genome AF: 0.0112 AC: 1704 AN: 152256 Hom.: 20 Cov.: 33 AF XY: 0.0104 AC XY: 772 AN XY: 74424

African (AFR) AF: 0.00313 AC: 130 AN: 41562

American (AMR) AF: 0.0112 AC: 172 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4814

European-Finnish (FIN) AF: 0.0104 AC: 110 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0173 AC: 1174 AN: 68014

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0150 Hom.: 71

Bravo AF: 0.0116

TwinsUK AF: 0.0191 AC: 71

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.00324 AC: 13

ESP6500EA AF: 0.0159 AC: 133

ExAC AF: 0.0102 AC: 1239

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0177

EpiControl AF: 0.0188

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	6	not provided (6)
-	-	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
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.96
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.20
Sift	Benign	0.14	T
Polyphen		0.90	P
Vest4		0.55
MPC		0.33
ClinPred		0.042	T
GERP RS		4.7
Mutation Taster		=89/11	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: rs62621206; hg19: chr2-179410282; COSMIC: COSV60066151; COSMIC: COSV60066151;