rs72648978

Variant names:

• chr2-178718590-G-A
• rs72648978
• NM_001267550.2:c.24516C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178718590-G-A
• chr2-178718590-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.24516C>T​(p.Thr8172Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,611,740 control chromosomes in the GnomAD database, including 8,963 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (614 hom., cov: 33)
  • Exomes 𝑓: 0.10 (8349 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: -1.84
• Publications: 7 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=-0.82).
• BP6: Variant 2-178718590-G-A is Benign according to our data. Variant chr2-178718590-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.85 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

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.24516C>T	p.Thr8172Thr	synonymous	Exon 85 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.23565C>T	p.Thr7855Thr	synonymous	Exon 83 of 313	NP_001243779.1
	TTN	NM_133378.4		c.20784C>T	p.Thr6928Thr	synonymous	Exon 82 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.24516C>T	p.Thr8172Thr	synonymous	Exon 85 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.24516C>T	p.Thr8172Thr	synonymous	Exon 85 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.24240C>T	p.Thr8080Thr	synonymous	Exon 83 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0894 AC: 13602 AN: 152070 Hom.: 614 Cov.: 33

Gnomad AFR AF: 0.0744

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0645

Gnomad ASJ AF: 0.0640

Gnomad EAS AF: 0.0216

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0996

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.0886

GnomAD2 exomes AF: 0.0878 AC: 21739 AN: 247616 AF XY: 0.0921

Gnomad AFR exome AF: 0.0757

Gnomad AMR exome AF: 0.0445

Gnomad ASJ exome AF: 0.0662

Gnomad EAS exome AF: 0.0205

Gnomad FIN exome AF: 0.0984

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.0937

GnomAD4 exome AF: 0.104 AC: 151913 AN: 1459552 Hom.: 8349 Cov.: 38 AF XY: 0.105 AC XY: 76004 AN XY: 725752

African (AFR) AF: 0.0718 AC: 2396 AN: 33360

American (AMR) AF: 0.0471 AC: 2099 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.0658 AC: 1716 AN: 26072

East Asian (EAS) AF: 0.0211 AC: 838 AN: 39658

South Asian (SAS) AF: 0.107 AC: 9173 AN: 86072

European-Finnish (FIN) AF: 0.0970 AC: 5173 AN: 53332

Middle Eastern (MID) AF: 0.0994 AC: 572 AN: 5752

European-Non Finnish (NFE) AF: 0.112 AC: 124074 AN: 1110438

Other (OTH) AF: 0.0974 AC: 5872 AN: 60268

GnomAD4 genome AF: 0.0895 AC: 13614 AN: 152188 Hom.: 614 Cov.: 33 AF XY: 0.0888 AC XY: 6608 AN XY: 74382

African (AFR) AF: 0.0742 AC: 3084 AN: 41540

American (AMR) AF: 0.0644 AC: 984 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0640 AC: 222 AN: 3470

East Asian (EAS) AF: 0.0216 AC: 112 AN: 5176

South Asian (SAS) AF: 0.104 AC: 501 AN: 4818

European-Finnish (FIN) AF: 0.0996 AC: 1057 AN: 10608

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7387 AN: 67978

Other (OTH) AF: 0.0877 AC: 185 AN: 2110

Alfa AF: 0.0983 Hom.: 529

Bravo AF: 0.0846

Asia WGS AF: 0.0650 AC: 224 AN: 3478

EpiCase AF: 0.106

EpiControl AF: 0.106

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.54
PhyloP100		-1.8
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs72648978; hg19: chr2-179583317; COSMIC: COSV60330608; COSMIC: COSV60330608;