rs72648266

Variant names:

• chr2-178542936-G-A
• rs72648266
• NM_001267550.2:c.96918C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178542936-G-A
• chr2-178542936-G-C
• chr2-178542936-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_001267550.2(TTN):​c.96918C>T​(p.Ile32306Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000665 in 1,600,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (0 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:15
• Conservation: PhyloP100: -0.0370
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-178542936-G-A is Benign according to our data. Variant chr2-178542936-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47573.
• BP7: Synonymous conserved (PhyloP=-0.037 with no splicing effect.

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.96918C>T	p.Ile32306Ile	synonymous	Exon 348 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.91995C>T	p.Ile30665Ile	synonymous	Exon 298 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.89214C>T	p.Ile29738Ile	synonymous	Exon 297 of 312	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.96918C>T	p.Ile32306Ile	synonymous	Exon 348 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.96762C>T	p.Ile32254Ile	synonymous	Exon 346 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.96642C>T	p.Ile32214Ile	synonymous	Exon 346 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00462

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000677 AC: 164 AN: 242192 AF XY: 0.000641

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000599

Gnomad ASJ exome AF: 0.00260

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.000512

GnomAD4 exome AF: 0.000667 AC: 966 AN: 1448506 Hom.: 0 Cov.: 32 AF XY: 0.000667 AC XY: 479 AN XY: 717984

African (AFR) AF: 0.000241 AC: 8 AN: 33164

American (AMR) AF: 0.000571 AC: 25 AN: 43792

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 72 AN: 25784

East Asian (EAS) AF: 0.00 AC: 0 AN: 39422

South Asian (SAS) AF: 0.0000472 AC: 4 AN: 84804

European-Finnish (FIN) AF: 0.000188 AC: 10 AN: 53210

Middle Eastern (MID) AF: 0.00192 AC: 11 AN: 5734

European-Non Finnish (NFE) AF: 0.000710 AC: 783 AN: 1102834

Other (OTH) AF: 0.000887 AC: 53 AN: 59762

GnomAD4 genome AF: 0.000651 AC: 99 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74372

African (AFR) AF: 0.000217 AC: 9 AN: 41530

American (AMR) AF: 0.000589 AC: 9 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00462 AC: 16 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000916 Hom.: 0

Bravo AF: 0.000691

EpiCase AF: 0.000928

EpiControl AF: 0.00143

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	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	-0.44
CADD	Benign	0.020
DANN	Benign	0.69
PhyloP100		-0.037
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs72648266; hg19: chr2-179407663;