rs72677244

Variant names:

• chr2-178614518-C-T
• rs72677244
• NM_001267550.2:c.48996G>A

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.48996G>A​(p.Glu16332Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,612,146 control chromosomes in the GnomAD database, including 959 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (180 hom., cov: 32)
  • Exomes 𝑓: 0.021 (779 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 0.380
• 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 2-178614518-C-T is Benign according to our data. Variant chr2-178614518-C-T is described in ClinVar as Benign. ClinVar VariationId is 47026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.124 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.48996G>A	p.Glu16332Glu	synonymous	Exon 261 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.44073G>A	p.Glu14691Glu	synonymous	Exon 211 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.41292G>A	p.Glu13764Glu	synonymous	Exon 210 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.48996G>A	p.Glu16332Glu	synonymous	Exon 261 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.48840G>A	p.Glu16280Glu	synonymous	Exon 259 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.48720G>A	p.Glu16240Glu	synonymous	Exon 259 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5635 AN: 151808 Hom.: 178 Cov.: 32

Gnomad AFR AF: 0.0698

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0276

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.0551

Gnomad FIN AF: 0.0420

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.0360

GnomAD2 exomes AF: 0.0336 AC: 8313 AN: 247488 AF XY: 0.0341

Gnomad AFR exome AF: 0.0696

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.0256

Gnomad EAS exome AF: 0.131

Gnomad FIN exome AF: 0.0408

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0290

GnomAD4 exome AF: 0.0207 AC: 30279 AN: 1460220 Hom.: 779 Cov.: 34 AF XY: 0.0218 AC XY: 15865 AN XY: 726394

African (AFR) AF: 0.0689 AC: 2300 AN: 33398

American (AMR) AF: 0.0147 AC: 656 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 663 AN: 26070

East Asian (EAS) AF: 0.135 AC: 5335 AN: 39468

South Asian (SAS) AF: 0.0576 AC: 4956 AN: 86114

European-Finnish (FIN) AF: 0.0404 AC: 2157 AN: 53336

Middle Eastern (MID) AF: 0.0421 AC: 242 AN: 5752

European-Non Finnish (NFE) AF: 0.0110 AC: 12176 AN: 1111176

Other (OTH) AF: 0.0298 AC: 1794 AN: 60286

GnomAD4 genome AF: 0.0372 AC: 5649 AN: 151926 Hom.: 180 Cov.: 32 AF XY: 0.0391 AC XY: 2904 AN XY: 74244

African (AFR) AF: 0.0698 AC: 2898 AN: 41506

American (AMR) AF: 0.0275 AC: 419 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3464

East Asian (EAS) AF: 0.132 AC: 675 AN: 5102

South Asian (SAS) AF: 0.0547 AC: 264 AN: 4824

European-Finnish (FIN) AF: 0.0420 AC: 445 AN: 10586

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0113 AC: 765 AN: 67888

Other (OTH) AF: 0.0380 AC: 80 AN: 2108

Alfa AF: 0.0213 Hom.: 37

Bravo AF: 0.0366

Asia WGS AF: 0.0880 AC: 304 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0154

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	1.5
DANN	Benign	0.78
PhyloP100		0.38
Mutation Taster		=78/22	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: rs72677244; hg19: chr2-179479245; COSMIC: COSV59894912; COSMIC: COSV59894912;