2-178583028-G-A

Variant names:

• chr2-178583028-G-A
• rs72646867
• NM_001267550.2:c.65775C>T

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.65775C>T​(p.Ser21925Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,609,056 control chromosomes in the GnomAD database, including 29 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 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (28 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:20
• Conservation: PhyloP100: -1.30
• Publications: 4 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=-0.46).
• BP6: Variant 2-178583028-G-A is Benign according to our data. Variant chr2-178583028-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47230.
• BP7: Synonymous conserved (PhyloP=-1.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00105 (160/152148) while in subpopulation SAS AF = 0.00933 (45/4824). AF 95% confidence interval is 0.00716. There are 1 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 28 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.65775C>T	p.Ser21925Ser	synonymous	Exon 313 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.60852C>T	p.Ser20284Ser	synonymous	Exon 263 of 313	NP_001243779.1
	TTN	NM_133378.4		c.58071C>T	p.Ser19357Ser	synonymous	Exon 262 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.65775C>T	p.Ser21925Ser	synonymous	Exon 313 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.65619C>T	p.Ser21873Ser	synonymous	Exon 311 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.65499C>T	p.Ser21833Ser	synonymous	Exon 311 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152030 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00953

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00245 AC: 602 AN: 245668 AF XY: 0.00296

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.00290

Gnomad EAS exome AF: 0.000399

Gnomad FIN exome AF: 0.000281

Gnomad NFE exome AF: 0.00160

Gnomad OTH exome AF: 0.00235

GnomAD4 exome AF: 0.00141 AC: 2056 AN: 1456908 Hom.: 28 Cov.: 30 AF XY: 0.00171 AC XY: 1240 AN XY: 724444

African (AFR) AF: 0.000240 AC: 8 AN: 33334

American (AMR) AF: 0.00155 AC: 69 AN: 44428

Ashkenazi Jewish (ASJ) AF: 0.00285 AC: 74 AN: 26010

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39334

South Asian (SAS) AF: 0.00979 AC: 836 AN: 85398

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53226

Middle Eastern (MID) AF: 0.00887 AC: 51 AN: 5748

European-Non Finnish (NFE) AF: 0.000782 AC: 868 AN: 1109280

Other (OTH) AF: 0.00229 AC: 138 AN: 60150

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152148 Hom.: 1 Cov.: 33 AF XY: 0.00128 AC XY: 95 AN XY: 74374

African (AFR) AF: 0.0000481 AC: 2 AN: 41546

American (AMR) AF: 0.00118 AC: 18 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5144

South Asian (SAS) AF: 0.00933 AC: 45 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 67968

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.00111

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00304

EpiControl AF: 0.00278

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.024
DANN	Benign	0.72
PhyloP100		-1.3
Mutation Taster		=95/5	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: rs72646867; hg19: chr2-179447755; COSMIC: COSV100620228; COSMIC: COSV100620228;