rs2288570

Variant names:

• chr2-178579562-A-G
• rs2288570
• NM_001267550.2:c.67635T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001256850.1(TTN):​c.62712T>C​(p.Val20904Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 1,612,998 control chromosomes in the GnomAD database, including 632 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (60 hom., cov: 32)
  • Exomes 𝑓: 0.025 (572 hom.)
• Consequence: TTN NM_001256850.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.00007531
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 1.03
• Publications: 8 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]

ENSG00000270574 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-178579562-A-G is Benign according to our data. Variant chr2-178579562-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0559 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256850.1. 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.67635T>C	p.Val22545Val	synonymous	Exon 319 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.62712T>C	p.Val20904Val	splice_region synonymous	Exon 269 of 313	NP_001243779.1
	TTN	NM_133378.4		c.59931T>C	p.Val19977Val	splice_region synonymous	Exon 268 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.67635T>C	p.Val22545Val	synonymous	Exon 319 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.67479T>C	p.Val22493Val	synonymous	Exon 317 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.67359T>C	p.Val22453Val	synonymous	Exon 317 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3352 AN: 152002 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0237

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.0614

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.0450

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0251

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.0299 AC: 7379 AN: 247152 AF XY: 0.0294

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.0346

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.0618

Gnomad FIN exome AF: 0.0478

Gnomad NFE exome AF: 0.0251

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0254 AC: 37164 AN: 1460878 Hom.: 572 Cov.: 34 AF XY: 0.0257 AC XY: 18652 AN XY: 726722

African (AFR) AF: 0.00449 AC: 150 AN: 33430

American (AMR) AF: 0.0327 AC: 1460 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 398 AN: 26112

East Asian (EAS) AF: 0.0636 AC: 2522 AN: 39662

South Asian (SAS) AF: 0.0279 AC: 2405 AN: 86230

European-Finnish (FIN) AF: 0.0492 AC: 2619 AN: 53178

Middle Eastern (MID) AF: 0.0143 AC: 82 AN: 5754

European-Non Finnish (NFE) AF: 0.0234 AC: 26034 AN: 1111466

Other (OTH) AF: 0.0248 AC: 1494 AN: 60342

GnomAD4 genome AF: 0.0220 AC: 3352 AN: 152120 Hom.: 60 Cov.: 32 AF XY: 0.0228 AC XY: 1694 AN XY: 74342

African (AFR) AF: 0.00467 AC: 194 AN: 41554

American (AMR) AF: 0.0237 AC: 361 AN: 15256

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

East Asian (EAS) AF: 0.0615 AC: 316 AN: 5136

South Asian (SAS) AF: 0.0317 AC: 153 AN: 4828

European-Finnish (FIN) AF: 0.0450 AC: 477 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0251 AC: 1707 AN: 67950

Other (OTH) AF: 0.0213 AC: 45 AN: 2114

Alfa AF: 0.0241 Hom.: 233

Bravo AF: 0.0196

Asia WGS AF: 0.0410 AC: 143 AN: 3476

EpiCase AF: 0.0230

EpiControl AF: 0.0244

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	3	not provided (3)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.7
DANN	Benign	0.68
PhyloP100		1.0
Mutation Taster		=65/35	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000075
dbscSNV1_RF	Benign	0.016
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: rs2288570; hg19: chr2-179444289;