chr2-178607966-A-G

Variant names:

• chr2-178607966-A-G
• rs2303831
• NM_001267550.2:c.52821T>C

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.52821T>C​(p.Asp17607Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 1,612,930 control chromosomes in the GnomAD database, including 646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (66 hom., cov: 32)
  • Exomes 𝑓: 0.024 (580 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 1.13
• Publications: 7 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-178607966-A-G is Benign according to our data. Variant chr2-178607966-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0883 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.52821T>C	p.Asp17607Asp	synonymous	Exon 276 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.47898T>C	p.Asp15966Asp	synonymous	Exon 226 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.45117T>C	p.Asp15039Asp	synonymous	Exon 225 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.52821T>C	p.Asp17607Asp	synonymous	Exon 276 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.52665T>C	p.Asp17555Asp	synonymous	Exon 274 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.52545T>C	p.Asp17515Asp	synonymous	Exon 274 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3277 AN: 151918 Hom.: 67 Cov.: 32

Gnomad AFR AF: 0.00466

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.0951

Gnomad SAS AF: 0.00954

Gnomad FIN AF: 0.0450

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0294 AC: 7313 AN: 248414 AF XY: 0.0278

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.0339

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.103

Gnomad FIN exome AF: 0.0475

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0279

GnomAD4 exome AF: 0.0240 AC: 35025 AN: 1460894 Hom.: 580 Cov.: 32 AF XY: 0.0236 AC XY: 17122 AN XY: 726744

African (AFR) AF: 0.00416 AC: 139 AN: 33422

American (AMR) AF: 0.0323 AC: 1443 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 374 AN: 26114

East Asian (EAS) AF: 0.0923 AC: 3651 AN: 39560

South Asian (SAS) AF: 0.00933 AC: 805 AN: 86238

European-Finnish (FIN) AF: 0.0490 AC: 2617 AN: 53396

Middle Eastern (MID) AF: 0.0116 AC: 67 AN: 5762

European-Non Finnish (NFE) AF: 0.0220 AC: 24494 AN: 1111388

Other (OTH) AF: 0.0238 AC: 1435 AN: 60324

GnomAD4 genome AF: 0.0215 AC: 3274 AN: 152036 Hom.: 66 Cov.: 32 AF XY: 0.0220 AC XY: 1638 AN XY: 74308

African (AFR) AF: 0.00465 AC: 193 AN: 41536

American (AMR) AF: 0.0233 AC: 356 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3470

East Asian (EAS) AF: 0.0953 AC: 488 AN: 5120

South Asian (SAS) AF: 0.00892 AC: 43 AN: 4820

European-Finnish (FIN) AF: 0.0450 AC: 477 AN: 10604

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0231 AC: 1572 AN: 67910

Other (OTH) AF: 0.0218 AC: 46 AN: 2112

Alfa AF: 0.0211 Hom.: 52

Bravo AF: 0.0200

Asia WGS AF: 0.0360 AC: 125 AN: 3476

EpiCase AF: 0.0201

EpiControl AF: 0.0219

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	-0.46
CADD	Benign	1.1
DANN	Benign	0.76
PhyloP100		1.1
Mutation Taster		=32/68	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: rs2303831; hg19: chr2-179472693; COSMIC: COSV60187895; COSMIC: COSV60187895;