rs72646865

Variant names:

• chr2-178583588-A-C
• rs72646865
• NM_001267550.2:c.65575+19T>G

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.65575+19T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,566,538 control chromosomes in the GnomAD database, including 674 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (90 hom., cov: 32)
  • Exomes 𝑓: 0.026 (584 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.423
• 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=-0.82).
• BP6: Variant 2-178583588-A-C is Benign according to our data. Variant chr2-178583588-A-C is described in ClinVar as Benign. ClinVar VariationId is 137800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.056 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.65575+19T>G		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.60652+19T>G		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.57871+19T>G		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.65575+19T>G		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.65419+19T>G		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.65299+19T>G		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 4896 AN: 151986 Hom.: 90 Cov.: 32

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0288

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.0615

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.0451

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0320

GnomAD2 exomes AF: 0.0322 AC: 7044 AN: 218768 AF XY: 0.0314

Gnomad AFR exome AF: 0.0401

Gnomad AMR exome AF: 0.0365

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.0601

Gnomad FIN exome AF: 0.0473

Gnomad NFE exome AF: 0.0248

Gnomad OTH exome AF: 0.0312

GnomAD4 exome AF: 0.0264 AC: 37321 AN: 1414434 Hom.: 584 Cov.: 31 AF XY: 0.0265 AC XY: 18478 AN XY: 697454

African (AFR) AF: 0.0392 AC: 1273 AN: 32444

American (AMR) AF: 0.0352 AC: 1418 AN: 40308

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 363 AN: 24152

East Asian (EAS) AF: 0.0629 AC: 2432 AN: 38686

South Asian (SAS) AF: 0.0274 AC: 2135 AN: 77902

European-Finnish (FIN) AF: 0.0491 AC: 2551 AN: 51932

Middle Eastern (MID) AF: 0.0167 AC: 83 AN: 4972

European-Non Finnish (NFE) AF: 0.0235 AC: 25480 AN: 1085688

Other (OTH) AF: 0.0272 AC: 1586 AN: 58350

GnomAD4 genome AF: 0.0322 AC: 4896 AN: 152104 Hom.: 90 Cov.: 32 AF XY: 0.0326 AC XY: 2426 AN XY: 74350

African (AFR) AF: 0.0391 AC: 1621 AN: 41504

American (AMR) AF: 0.0287 AC: 439 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3472

East Asian (EAS) AF: 0.0616 AC: 316 AN: 5130

South Asian (SAS) AF: 0.0318 AC: 153 AN: 4816

European-Finnish (FIN) AF: 0.0451 AC: 479 AN: 10610

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0253 AC: 1720 AN: 67980

Other (OTH) AF: 0.0317 AC: 67 AN: 2114

Alfa AF: 0.0256 Hom.: 25

Bravo AF: 0.0315

Asia WGS AF: 0.0430 AC: 148 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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	-0.82
CADD	Benign	0.75
DANN	Benign	0.67
PhyloP100		-0.42
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: rs72646865; hg19: chr2-179448315; COSMIC: COSV60109379; COSMIC: COSV60109379;