rs3731750

Variant names:

• chr2-178541276-C-A
• rs3731750
• NM_001267550.2:c.97795+6G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178541276-C-A
• chr2-178541276-C-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.97795+6G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,484,278 control chromosomes in the GnomAD database, including 64,894 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11647 hom., cov: 33)
  • Exomes 𝑓: 0.26 (53247 hom.)
• Consequence: TTN NM_001267550.2 splice_region, intron
• Scores: Splicing: ADA: 0.00001107
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 1.01
• Publications: 17 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]

ENSG00000270956 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 2-178541276-C-A is Benign according to our data. Variant chr2-178541276-C-A is described in ClinVar as Benign. ClinVar VariationId is 47590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.679 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.97795+6G>T		splice_region intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.92872+6G>T		splice_region intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.90091+6G>T		splice_region 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.97795+6G>T		splice_region intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.97639+6G>T		splice_region intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.97519+6G>T		splice_region intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54400 AN: 151900 Hom.: 11598 Cov.: 33

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.698

Gnomad SAS AF: 0.515

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.325

GnomAD2 exomes AF: 0.351 AC: 44481 AN: 126840 AF XY: 0.351

Gnomad AFR exome AF: 0.537

Gnomad AMR exome AF: 0.413

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.702

Gnomad FIN exome AF: 0.275

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.259 AC: 344812 AN: 1332260 Hom.: 53247 Cov.: 31 AF XY: 0.263 AC XY: 170755 AN XY: 649142

African (AFR) AF: 0.547 AC: 16663 AN: 30462

American (AMR) AF: 0.415 AC: 13049 AN: 31424

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 5905 AN: 21618

East Asian (EAS) AF: 0.690 AC: 24044 AN: 34838

South Asian (SAS) AF: 0.492 AC: 32560 AN: 66204

European-Finnish (FIN) AF: 0.275 AC: 13022 AN: 47284

Middle Eastern (MID) AF: 0.301 AC: 1628 AN: 5406

European-Non Finnish (NFE) AF: 0.213 AC: 221469 AN: 1039886

Other (OTH) AF: 0.299 AC: 16472 AN: 55138

GnomAD4 genome AF: 0.359 AC: 54510 AN: 152018 Hom.: 11647 Cov.: 33 AF XY: 0.368 AC XY: 27361 AN XY: 74320

African (AFR) AF: 0.535 AC: 22155 AN: 41434

American (AMR) AF: 0.382 AC: 5825 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 985 AN: 3468

East Asian (EAS) AF: 0.698 AC: 3609 AN: 5170

South Asian (SAS) AF: 0.513 AC: 2477 AN: 4824

European-Finnish (FIN) AF: 0.285 AC: 3015 AN: 10572

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15148 AN: 67976

Other (OTH) AF: 0.333 AC: 701 AN: 2108

Alfa AF: 0.261 Hom.: 11026

Bravo AF: 0.372

Asia WGS AF: 0.618 AC: 2147 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.84
PhyloP100		1.0
Mutation Taster		=74/26	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.060
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: rs3731750; hg19: chr2-179406003; COSMIC: COSV59878103; COSMIC: COSV59878103;