rs73036398

Variant names:

• chr2-178607870-A-G
• rs73036398
• NM_001267550.2:c.52917T>C

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.52917T>C​(p.Asp17639Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00452 in 1,612,964 control chromosomes in the GnomAD database, including 227 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 (119 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (108 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 1.14
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-178607870-A-G is Benign according to our data. Variant chr2-178607870-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0706 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.52917T>C	p.Asp17639Asp	synonymous	Exon 276 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.47994T>C	p.Asp15998Asp	synonymous	Exon 226 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.45213T>C	p.Asp15071Asp	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.52917T>C	p.Asp17639Asp	synonymous	Exon 276 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.52761T>C	p.Asp17587Asp	synonymous	Exon 274 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.52641T>C	p.Asp17547Asp	synonymous	Exon 274 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3291 AN: 151898 Hom.: 117 Cov.: 33

Gnomad AFR AF: 0.0728

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000780

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00609 AC: 1512 AN: 248460 AF XY: 0.00459

Gnomad AFR exome AF: 0.0733

Gnomad AMR exome AF: 0.00493

Gnomad ASJ exome AF: 0.00736

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000943

Gnomad OTH exome AF: 0.00415

GnomAD4 exome AF: 0.00273 AC: 3992 AN: 1460948 Hom.: 108 Cov.: 32 AF XY: 0.00241 AC XY: 1754 AN XY: 726784

African (AFR) AF: 0.0741 AC: 2476 AN: 33426

American (AMR) AF: 0.00544 AC: 243 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00854 AC: 223 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86244

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53400

Middle Eastern (MID) AF: 0.00660 AC: 38 AN: 5760

European-Non Finnish (NFE) AF: 0.000577 AC: 641 AN: 1111406

Other (OTH) AF: 0.00600 AC: 362 AN: 60322

GnomAD4 genome AF: 0.0217 AC: 3301 AN: 152016 Hom.: 119 Cov.: 33 AF XY: 0.0208 AC XY: 1548 AN XY: 74286

African (AFR) AF: 0.0728 AC: 3021 AN: 41498

American (AMR) AF: 0.0107 AC: 163 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000780 AC: 53 AN: 67906

Other (OTH) AF: 0.0156 AC: 33 AN: 2112

Alfa AF: 0.0109 Hom.: 38

Bravo AF: 0.0251

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00154

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.1
DANN	Benign	0.64
PhyloP100		1.1
Mutation Taster		=79/21	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs73036398; hg19: chr2-179472597;