rs72646842

Variant names:

• chr2-178592069-G-A
• rs72646842
• NM_001267550.2:c.59835C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178592069-G-A
• chr2-178592069-G-C
• chr2-178592069-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001267550.2(TTN):​c.59835C>T​(p.Asn19945Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,613,026 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00089 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (2 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:12
• Conservation: PhyloP100: 0.273
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-178592069-G-A is Benign according to our data. Variant chr2-178592069-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47155.
• BP7: Synonymous conserved (PhyloP=0.273 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000894 (136/152152) while in subpopulation AFR AF = 0.00318 (132/41540). AF 95% confidence interval is 0.00274. There are 1 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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.59835C>T	p.Asn19945Asn	synonymous	Exon 302 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.54912C>T	p.Asn18304Asn	synonymous	Exon 252 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.52131C>T	p.Asn17377Asn	synonymous	Exon 251 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.59835C>T	p.Asn19945Asn	synonymous	Exon 302 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.59679C>T	p.Asn19893Asn	synonymous	Exon 300 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.59559C>T	p.Asn19853Asn	synonymous	Exon 300 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000888 AC: 135 AN: 152034 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000258 AC: 64 AN: 247850 AF XY: 0.000193

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000107 AC: 156 AN: 1460874 Hom.: 2 Cov.: 35 AF XY: 0.0000949 AC XY: 69 AN XY: 726700

African (AFR) AF: 0.00395 AC: 132 AN: 33454

American (AMR) AF: 0.000224 AC: 10 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39476

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111532

Other (OTH) AF: 0.000199 AC: 12 AN: 60324

GnomAD4 genome AF: 0.000894 AC: 136 AN: 152152 Hom.: 1 Cov.: 32 AF XY: 0.000861 AC XY: 64 AN XY: 74372

African (AFR) AF: 0.00318 AC: 132 AN: 41540

American (AMR) AF: 0.000196 AC: 3 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67970

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000414 Hom.: 0

Bravo AF: 0.000960

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.48
DANN	Benign	0.87
PhyloP100		0.27
Mutation Taster		=88/12	polymorphism

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: rs72646842; hg19: chr2-179456796; COSMIC: COSV104645139;