rs72677223

Variant names:

• chr2-178621551-G-A
• rs72677223
• NM_001267550.2:c.45273C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178621551-G-A
• chr2-178621551-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_001267550.2(TTN):​c.45273C>T​(p.Asn15091Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,612,306 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:15
• Conservation: PhyloP100: -0.0110
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-178621551-G-A is Benign according to our data. Variant chr2-178621551-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178211.
• BP7: Synonymous conserved (PhyloP=-0.011 with no splicing effect.

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.45273C>T	p.Asn15091Asn	synonymous	Exon 245 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.40350C>T	p.Asn13450Asn	synonymous	Exon 195 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.37569C>T	p.Asn12523Asn	synonymous	Exon 194 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.45273C>T	p.Asn15091Asn	synonymous	Exon 245 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.45117C>T	p.Asn15039Asn	synonymous	Exon 243 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.44997C>T	p.Asn14999Asn	synonymous	Exon 243 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 39 AN: 151794 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

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: 0.000516

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000339 AC: 84 AN: 247886 AF XY: 0.000335

Gnomad AFR exome AF: 0.000129

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: 0.000642

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000329 AC: 480 AN: 1460512 Hom.: 0 Cov.: 32 AF XY: 0.000329 AC XY: 239 AN XY: 726566

African (AFR) AF: 0.0000599 AC: 2 AN: 33408

American (AMR) AF: 0.000134 AC: 6 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86230

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53382

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.000398 AC: 442 AN: 1111194

Other (OTH) AF: 0.000282 AC: 17 AN: 60302

GnomAD4 genome AF: 0.000257 AC: 39 AN: 151794 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74102

African (AFR) AF: 0.0000483 AC: 2 AN: 41368

American (AMR) AF: 0.000132 AC: 2 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000516 AC: 35 AN: 67890

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000337 Hom.: 0

Bravo AF: 0.000317

EpiCase AF: 0.000709

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	-	4	not specified (4)
-	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	Cardiomyopathy (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	-0.44
CADD	Benign	0.14
DANN	Benign	0.80
PhyloP100		-0.011
Mutation Taster		=98/2	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: rs72677223; hg19: chr2-179486278; COSMIC: COSV100617069; COSMIC: COSV100617069;