rs72646852

Variant names:

• chr2-178588560-C-T
• rs72646852
• NM_001267550.2:c.63165G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001267550.2(TTN):​c.63165G>A​(p.Pro21055Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,531,202 control chromosomes in the GnomAD database, including 5 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 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (5 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:16
• Conservation: PhyloP100: 0.108
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 2-178588560-C-T is Benign according to our data. Variant chr2-178588560-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47191.
• BP7: Synonymous conserved (PhyloP=0.108 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0015 (2062/1379094) while in subpopulation NFE AF = 0.00167 (1791/1075022). AF 95% confidence interval is 0.0016. There are 5 homozygotes in GnomAdExome4. There are 989 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.63165G>A	p.Pro21055Pro	synonymous	Exon 304 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.58242G>A	p.Pro19414Pro	synonymous	Exon 254 of 313	NP_001243779.1
	TTN	NM_133378.4		c.55461G>A	p.Pro18487Pro	synonymous	Exon 253 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.63165G>A	p.Pro21055Pro	synonymous	Exon 304 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.63009G>A	p.Pro21003Pro	synonymous	Exon 302 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.62889G>A	p.Pro20963Pro	synonymous	Exon 302 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000985

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00108 AC: 198 AN: 183752 AF XY: 0.00108

Gnomad AFR exome AF: 0.000341

Gnomad AMR exome AF: 0.000968

Gnomad ASJ exome AF: 0.00925

Gnomad EAS exome AF: 0.0000629

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.00150 AC: 2062 AN: 1379094 Hom.: 5 Cov.: 32 AF XY: 0.00146 AC XY: 989 AN XY: 677496

African (AFR) AF: 0.000196 AC: 6 AN: 30650

American (AMR) AF: 0.000828 AC: 26 AN: 31406

Ashkenazi Jewish (ASJ) AF: 0.00623 AC: 129 AN: 20700

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39094

South Asian (SAS) AF: 0.0000574 AC: 4 AN: 69702

European-Finnish (FIN) AF: 0.0000595 AC: 3 AN: 50396

Middle Eastern (MID) AF: 0.000186 AC: 1 AN: 5374

European-Non Finnish (NFE) AF: 0.00167 AC: 1791 AN: 1075022

Other (OTH) AF: 0.00178 AC: 101 AN: 56750

GnomAD4 genome AF: 0.00103 AC: 157 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74346

African (AFR) AF: 0.000289 AC: 12 AN: 41536

American (AMR) AF: 0.000983 AC: 15 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00149 AC: 101 AN: 67972

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00168 Hom.: 4

Bravo AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (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	-0.42
CADD	Benign	2.6
DANN	Benign	0.79
PhyloP100		0.11
Mutation Taster		=94/6	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: rs72646852; hg19: chr2-179453287;