rs2562849

Variant names:

• chr2-178664546-A-G
• rs2562849
• NM_001267550.2:c.36203-9T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178664546-A-G
• chr2-178664546-A-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.36203-9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 1,608,246 control chromosomes in the GnomAD database, including 743 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (76 hom., cov: 31)
  • Exomes 𝑓: 0.026 (667 hom.)
• Consequence: TTN NM_001267550.2 intron
• Scores: Splicing: ADA: 0.0005297
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.63
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-178664546-A-G is Benign according to our data. Variant chr2-178664546-A-G is described in ClinVar as Benign. ClinVar VariationId is 413235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0882 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.36203-9T>C		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34265-1491T>C		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31484-1491T>C		intron	N/A	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.36203-9T>C		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.36203-9T>C		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.35927-9T>C		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3540 AN: 152106 Hom.: 76 Cov.: 31

Gnomad AFR AF: 0.00490

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0252

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.0949

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0453

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0335 AC: 7924 AN: 236650 AF XY: 0.0326

Gnomad AFR exome AF: 0.00522

Gnomad AMR exome AF: 0.0353

Gnomad ASJ exome AF: 0.0155

Gnomad EAS exome AF: 0.103

Gnomad FIN exome AF: 0.0478

Gnomad NFE exome AF: 0.0254

Gnomad OTH exome AF: 0.0312

GnomAD4 exome AF: 0.0260 AC: 37787 AN: 1456022 Hom.: 667 Cov.: 31 AF XY: 0.0261 AC XY: 18911 AN XY: 724364

African (AFR) AF: 0.00468 AC: 155 AN: 33106

American (AMR) AF: 0.0331 AC: 1454 AN: 43978

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 395 AN: 25968

East Asian (EAS) AF: 0.0912 AC: 3618 AN: 39674

South Asian (SAS) AF: 0.0283 AC: 2418 AN: 85350

European-Finnish (FIN) AF: 0.0492 AC: 2569 AN: 52240

Middle Eastern (MID) AF: 0.0145 AC: 83 AN: 5736

European-Non Finnish (NFE) AF: 0.0230 AC: 25504 AN: 1109790

Other (OTH) AF: 0.0264 AC: 1591 AN: 60180

GnomAD4 genome AF: 0.0233 AC: 3540 AN: 152224 Hom.: 76 Cov.: 31 AF XY: 0.0241 AC XY: 1790 AN XY: 74416

African (AFR) AF: 0.00489 AC: 203 AN: 41550

American (AMR) AF: 0.0252 AC: 384 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3468

East Asian (EAS) AF: 0.0951 AC: 492 AN: 5174

South Asian (SAS) AF: 0.0315 AC: 152 AN: 4818

European-Finnish (FIN) AF: 0.0453 AC: 480 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0247 AC: 1682 AN: 68022

Other (OTH) AF: 0.0232 AC: 49 AN: 2116

Alfa AF: 0.0180 Hom.: 20

Bravo AF: 0.0209

Asia WGS AF: 0.0480 AC: 167 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.67
PhyloP100		2.6
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00053
dbscSNV1_RF	Benign	0.084
SpliceAI score (max)		0.010		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: rs2562849; hg19: chr2-179529273; COSMIC: COSV60187943;