chr2-178678490-C-T

Variant names:

• chr2-178678490-C-T
• rs35112591
• NM_001267550.2:c.33834G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.33834G>A​(p.Glu11278Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,574,886 control chromosomes in the GnomAD database, including 25,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2618 hom., cov: 32)
  • Exomes 𝑓: 0.17 (23001 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -1.10
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 2-178678490-C-T is Benign according to our data. Variant chr2-178678490-C-T is described in ClinVar as Benign. ClinVar VariationId is 46894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 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.33834G>A	p.Glu11278Glu	synonymous	Exon 144 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.32883G>A	p.Glu10961Glu	synonymous	Exon 142 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.30102G>A	p.Glu10034Glu	synonymous	Exon 141 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.33834G>A	p.Glu11278Glu	synonymous	Exon 144 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.33834G>A	p.Glu11278Glu	synonymous	Exon 144 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.33558G>A	p.Glu11186Glu	synonymous	Exon 142 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25853 AN: 151402 Hom.: 2613 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.179

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.177

GnomAD2 exomes AF: 0.189 AC: 37687 AN: 199310 AF XY: 0.193

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.438

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.170 AC: 241459 AN: 1423368 Hom.: 23001 Cov.: 31 AF XY: 0.172 AC XY: 121299 AN XY: 705046

African (AFR) AF: 0.142 AC: 4536 AN: 31890

American (AMR) AF: 0.174 AC: 6415 AN: 36942

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 5280 AN: 25242

East Asian (EAS) AF: 0.458 AC: 17615 AN: 38452

South Asian (SAS) AF: 0.260 AC: 20261 AN: 77972

European-Finnish (FIN) AF: 0.123 AC: 6396 AN: 52076

Middle Eastern (MID) AF: 0.215 AC: 1222 AN: 5696

European-Non Finnish (NFE) AF: 0.154 AC: 168971 AN: 1096126

Other (OTH) AF: 0.183 AC: 10763 AN: 58972

GnomAD4 genome AF: 0.171 AC: 25877 AN: 151518 Hom.: 2618 Cov.: 32 AF XY: 0.174 AC XY: 12889 AN XY: 74008

African (AFR) AF: 0.143 AC: 5901 AN: 41346

American (AMR) AF: 0.166 AC: 2512 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 723 AN: 3458

East Asian (EAS) AF: 0.453 AC: 2327 AN: 5132

South Asian (SAS) AF: 0.272 AC: 1305 AN: 4806

European-Finnish (FIN) AF: 0.136 AC: 1425 AN: 10508

Middle Eastern (MID) AF: 0.190 AC: 55 AN: 290

European-Non Finnish (NFE) AF: 0.160 AC: 10816 AN: 67810

Other (OTH) AF: 0.184 AC: 383 AN: 2084

Alfa AF: 0.167 Hom.: 2200

Bravo AF: 0.174

Asia WGS AF: 0.355 AC: 1235 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	not provided (2)
-	-	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	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	-0.33
CADD	Benign	1.2
DANN	Benign	0.79
PhyloP100		-1.1
Mutation Taster		=91/9	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: rs35112591; hg19: chr2-179543217; COSMIC: COSV59921580;