rs9808036

Variant names:

• chr2-178556882-C-T
• rs9808036
• NM_001267550.2:c.88272G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178556882-C-T
• chr2-178556882-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.88272G>A​(p.Glu29424Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0462 in 1,613,688 control chromosomes in the GnomAD database, including 3,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (373 hom., cov: 33)
  • Exomes 𝑓: 0.046 (3117 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: -1.04
• 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]

ENSG00000279598 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-178556882-C-T is Benign according to our data. Variant chr2-178556882-C-T is described in ClinVar as Benign. ClinVar VariationId is 47476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.166 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.88272G>A	p.Glu29424Glu	synonymous	Exon 330 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.83349G>A	p.Glu27783Glu	synonymous	Exon 280 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.80568G>A	p.Glu26856Glu	synonymous	Exon 279 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.88272G>A	p.Glu29424Glu	synonymous	Exon 330 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.88116G>A	p.Glu29372Glu	synonymous	Exon 328 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.87996G>A	p.Glu29332Glu	synonymous	Exon 328 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0501 AC: 7617 AN: 152136 Hom.: 367 Cov.: 33

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.0241

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.0585

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0304

Gnomad OTH AF: 0.0440

GnomAD2 exomes AF: 0.0756 AC: 18765 AN: 248364 AF XY: 0.0755

Gnomad AFR exome AF: 0.0326

Gnomad AMR exome AF: 0.195

Gnomad ASJ exome AF: 0.0298

Gnomad EAS exome AF: 0.0275

Gnomad FIN exome AF: 0.0574

Gnomad NFE exome AF: 0.0323

Gnomad OTH exome AF: 0.0597

GnomAD4 exome AF: 0.0458 AC: 66996 AN: 1461434 Hom.: 3117 Cov.: 32 AF XY: 0.0489 AC XY: 35526 AN XY: 726998

African (AFR) AF: 0.0318 AC: 1065 AN: 33476

American (AMR) AF: 0.191 AC: 8539 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0293 AC: 765 AN: 26132

East Asian (EAS) AF: 0.0138 AC: 546 AN: 39634

South Asian (SAS) AF: 0.173 AC: 14942 AN: 86250

European-Finnish (FIN) AF: 0.0588 AC: 3133 AN: 53324

Middle Eastern (MID) AF: 0.0472 AC: 272 AN: 5766

European-Non Finnish (NFE) AF: 0.0313 AC: 34768 AN: 1111780

Other (OTH) AF: 0.0491 AC: 2966 AN: 60366

GnomAD4 genome AF: 0.0501 AC: 7630 AN: 152254 Hom.: 373 Cov.: 33 AF XY: 0.0567 AC XY: 4219 AN XY: 74444

African (AFR) AF: 0.0331 AC: 1374 AN: 41556

American (AMR) AF: 0.153 AC: 2335 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3472

East Asian (EAS) AF: 0.0243 AC: 126 AN: 5184

South Asian (SAS) AF: 0.176 AC: 849 AN: 4826

European-Finnish (FIN) AF: 0.0585 AC: 620 AN: 10600

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0304 AC: 2067 AN: 68006

Other (OTH) AF: 0.0435 AC: 92 AN: 2114

Alfa AF: 0.0357 Hom.: 330

Bravo AF: 0.0517

Asia WGS AF: 0.110 AC: 382 AN: 3476

EpiCase AF: 0.0304

EpiControl AF: 0.0312

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.6
DANN	Benign	0.68
PhyloP100		-1.0
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: rs9808036; hg19: chr2-179421609; COSMIC: COSV60092357;