rs72955212

Variant names:

• chr2-178756457-G-A
• rs72955212
• NM_001267550.2:c.11019C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178756457-G-A
• chr2-178756457-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.11019C>T​(p.Cys3673Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,613,732 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (22 hom., cov: 32)
  • Exomes 𝑓: 0.014 (163 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.0220
• 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=-0.88).
• BP6: Variant 2-178756457-G-A is Benign according to our data. Variant chr2-178756457-G-A is described in ClinVar as Benign. ClinVar VariationId is 47850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.022 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0102 (1554/152276) while in subpopulation NFE AF = 0.0156 (1064/68018). AF 95% confidence interval is 0.0149. There are 22 homozygotes in GnomAd4. There are 743 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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.11019C>T	p.Cys3673Cys	synonymous	Exon 46 of 363	NP_001254479.2
	TTN	NM_133437.4		c.10506C>T	p.Cys3502Cys	synonymous	Exon 44 of 192	NP_597681.4
	TTN	NM_001256850.1		c.10303+2527C>T		intron	N/A	NP_001243779.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.11019C>T	p.Cys3673Cys	synonymous	Exon 46 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.11019C>T	p.Cys3673Cys	synonymous	Exon 46 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.10743C>T	p.Cys3581Cys	synonymous	Exon 44 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1555 AN: 152158 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0236

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.0111 AC: 2750 AN: 248618 AF XY: 0.0108

Gnomad AFR exome AF: 0.00245

Gnomad AMR exome AF: 0.00453

Gnomad ASJ exome AF: 0.00607

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0243

Gnomad NFE exome AF: 0.0166

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0139 AC: 20321 AN: 1461456 Hom.: 163 Cov.: 33 AF XY: 0.0135 AC XY: 9808 AN XY: 727030

African (AFR) AF: 0.00176 AC: 59 AN: 33468

American (AMR) AF: 0.00463 AC: 207 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00650 AC: 170 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39650

South Asian (SAS) AF: 0.00124 AC: 107 AN: 86256

European-Finnish (FIN) AF: 0.0248 AC: 1322 AN: 53328

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5766

European-Non Finnish (NFE) AF: 0.0159 AC: 17712 AN: 1111782

Other (OTH) AF: 0.0116 AC: 702 AN: 60368

GnomAD4 genome AF: 0.0102 AC: 1554 AN: 152276 Hom.: 22 Cov.: 32 AF XY: 0.00998 AC XY: 743 AN XY: 74462

African (AFR) AF: 0.00250 AC: 104 AN: 41562

American (AMR) AF: 0.00550 AC: 84 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0236 AC: 251 AN: 10618

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0156 AC: 1064 AN: 68018

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.0137 Hom.: 12

Bravo AF: 0.00872

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0137

EpiControl AF: 0.0146

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	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	-0.88
CADD	Benign	0.061
DANN	Benign	0.72
PhyloP100		0.022
Mutation Taster		=99/1	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: rs72955212; hg19: chr2-179621184; COSMIC: COSV60293610; COSMIC: COSV60293610;