2-178714967-T-A

Variant names:

• chr2-178714967-T-A
• rs2562837
• NM_001267550.2:c.26200+19A>T

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.26200+19A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.033 in 1,589,382 control chromosomes in the GnomAD database, including 1,676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (249 hom., cov: 32)
  • Exomes 𝑓: 0.032 (1427 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.118
• Publications: 5 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 (BayesDel_noAF=-0.85).
• BP6: Variant 2-178714967-T-A is Benign according to our data. Variant chr2-178714967-T-A is described in ClinVar as Benign. ClinVar VariationId is 137847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 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.26200+19A>T		intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.25249+19A>T		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.22468+19A>T		intron	N/A	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.26200+19A>T		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.26200+19A>T		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.25924+19A>T		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0451 AC: 6860 AN: 151978 Hom.: 250 Cov.: 32

Gnomad AFR AF: 0.0640

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0365

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.0363

Gnomad FIN AF: 0.0477

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0445

GnomAD2 exomes AF: 0.0487 AC: 11153 AN: 229132 AF XY: 0.0453

Gnomad AFR exome AF: 0.0652

Gnomad AMR exome AF: 0.0451

Gnomad ASJ exome AF: 0.0303

Gnomad EAS exome AF: 0.211

Gnomad FIN exome AF: 0.0493

Gnomad NFE exome AF: 0.0261

Gnomad OTH exome AF: 0.0378

GnomAD4 exome AF: 0.0317 AC: 45539 AN: 1437286 Hom.: 1427 Cov.: 31 AF XY: 0.0314 AC XY: 22330 AN XY: 711446

African (AFR) AF: 0.0619 AC: 2047 AN: 33090

American (AMR) AF: 0.0433 AC: 1887 AN: 43578

Ashkenazi Jewish (ASJ) AF: 0.0321 AC: 780 AN: 24324

East Asian (EAS) AF: 0.191 AC: 7539 AN: 39508

South Asian (SAS) AF: 0.0300 AC: 2414 AN: 80450

European-Finnish (FIN) AF: 0.0514 AC: 2684 AN: 52258

Middle Eastern (MID) AF: 0.0168 AC: 95 AN: 5638

European-Non Finnish (NFE) AF: 0.0236 AC: 25965 AN: 1099012

Other (OTH) AF: 0.0358 AC: 2128 AN: 59428

GnomAD4 genome AF: 0.0451 AC: 6856 AN: 152096 Hom.: 249 Cov.: 32 AF XY: 0.0458 AC XY: 3407 AN XY: 74340

African (AFR) AF: 0.0638 AC: 2648 AN: 41500

American (AMR) AF: 0.0365 AC: 557 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 127 AN: 3470

East Asian (EAS) AF: 0.191 AC: 983 AN: 5142

South Asian (SAS) AF: 0.0363 AC: 175 AN: 4818

European-Finnish (FIN) AF: 0.0477 AC: 506 AN: 10604

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0255 AC: 1736 AN: 67966

Other (OTH) AF: 0.0431 AC: 91 AN: 2112

Alfa AF: 0.0189 Hom.: 8

Bravo AF: 0.0470

Asia WGS AF: 0.0850 AC: 293 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	not provided (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.4
DANN	Benign	0.70
PhyloP100		0.12
Mutation Taster		=100/0	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: rs2562837; hg19: chr2-179579694; COSMIC: COSV59946407; COSMIC: COSV59946407;