chr2-178714003-G-A

Variant names:

• chr2-178714003-G-A
• rs2562839
• NM_001267550.2:c.26655C>T

Variant summary

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

The NM_001267550.2(TTN):​c.26655C>T​(p.Ser8885Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,612,968 control chromosomes in the GnomAD database, including 58,094 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8232 hom., cov: 32)
  • Exomes 𝑓: 0.24 (49862 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.617
• Publications: 18 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]

LOC124906100 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 2-178714003-G-A is Benign according to our data. Variant chr2-178714003-G-A is described in ClinVar as Benign. ClinVar VariationId is 46784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.617 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.632 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.26655C>T	p.Ser8885Ser	synonymous	Exon 92 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.25704C>T	p.Ser8568Ser	synonymous	Exon 90 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.22923C>T	p.Ser7641Ser	synonymous	Exon 89 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.26655C>T	p.Ser8885Ser	synonymous	Exon 92 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.26655C>T	p.Ser8885Ser	synonymous	Exon 92 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.26379C>T	p.Ser8793Ser	synonymous	Exon 90 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46295 AN: 151826 Hom.: 8196 Cov.: 32

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.650

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.291

GnomAD2 exomes AF: 0.308 AC: 76416 AN: 248130 AF XY: 0.303

Gnomad AFR exome AF: 0.421

Gnomad AMR exome AF: 0.412

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.668

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.241 AC: 351913 AN: 1461024 Hom.: 49862 Cov.: 35 AF XY: 0.244 AC XY: 177380 AN XY: 726758

African (AFR) AF: 0.429 AC: 14358 AN: 33458

American (AMR) AF: 0.409 AC: 18272 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 5228 AN: 26128

East Asian (EAS) AF: 0.648 AC: 25694 AN: 39656

South Asian (SAS) AF: 0.419 AC: 36111 AN: 86210

European-Finnish (FIN) AF: 0.204 AC: 10879 AN: 53348

Middle Eastern (MID) AF: 0.268 AC: 1544 AN: 5766

European-Non Finnish (NFE) AF: 0.202 AC: 224010 AN: 1111492

Other (OTH) AF: 0.262 AC: 15817 AN: 60340

GnomAD4 genome AF: 0.305 AC: 46386 AN: 151944 Hom.: 8232 Cov.: 32 AF XY: 0.312 AC XY: 23141 AN XY: 74250

African (AFR) AF: 0.423 AC: 17519 AN: 41424

American (AMR) AF: 0.359 AC: 5473 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 704 AN: 3468

East Asian (EAS) AF: 0.650 AC: 3339 AN: 5136

South Asian (SAS) AF: 0.432 AC: 2080 AN: 4820

European-Finnish (FIN) AF: 0.205 AC: 2166 AN: 10574

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.205 AC: 13934 AN: 67950

Other (OTH) AF: 0.293 AC: 619 AN: 2112

Alfa AF: 0.245 Hom.: 8988

Bravo AF: 0.323

Asia WGS AF: 0.533 AC: 1853 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	7.4
DANN	Benign	0.76
PhyloP100		0.62
Mutation Taster		=82/18	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: rs2562839; hg19: chr2-179578730; COSMIC: COSV59929863; COSMIC: COSV59929863;