rs55977045

Variant names:

• chr2-178539470-T-C
• rs55977045
• NM_001267550.2:c.98595A>G

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.98595A>G​(p.Glu32865Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,613,848 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (15 hom., cov: 32)
  • Exomes 𝑓: 0.015 (198 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 0.267
• Publications: 3 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=-0.58).
• BP6: Variant 2-178539470-T-C is Benign according to our data. Variant chr2-178539470-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.267 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0115 (1746/152274) while in subpopulation NFE AF = 0.0181 (1228/68002). AF 95% confidence interval is 0.0172. There are 15 homozygotes in GnomAd4. There are 799 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.98595A>G	p.Glu32865Glu	synonymous	Exon 352 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.93672A>G	p.Glu31224Glu	synonymous	Exon 302 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.90891A>G	p.Glu30297Glu	synonymous	Exon 301 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.98595A>G	p.Glu32865Glu	synonymous	Exon 352 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.98439A>G	p.Glu32813Glu	synonymous	Exon 350 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.98319A>G	p.Glu32773Glu	synonymous	Exon 350 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1746 AN: 152156 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00894

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0113 AC: 2804 AN: 249006 AF XY: 0.0113

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.00811

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0101

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0149 AC: 21813 AN: 1461574 Hom.: 198 Cov.: 33 AF XY: 0.0147 AC XY: 10693 AN XY: 727072

African (AFR) AF: 0.00299 AC: 100 AN: 33468

American (AMR) AF: 0.00801 AC: 358 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0125 AC: 326 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00224 AC: 193 AN: 86256

European-Finnish (FIN) AF: 0.0106 AC: 568 AN: 53400

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5766

European-Non Finnish (NFE) AF: 0.0175 AC: 19426 AN: 1111774

Other (OTH) AF: 0.0137 AC: 828 AN: 60368

GnomAD4 genome AF: 0.0115 AC: 1746 AN: 152274 Hom.: 15 Cov.: 32 AF XY: 0.0107 AC XY: 799 AN XY: 74452

African (AFR) AF: 0.00327 AC: 136 AN: 41564

American (AMR) AF: 0.0112 AC: 171 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.00894 AC: 95 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0181 AC: 1228 AN: 68002

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.0160 Hom.: 27

Bravo AF: 0.0112

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0170

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	4	not provided (4)
-	-	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	Tibial muscular dystrophy (2)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.12
DANN	Benign	0.69
PhyloP100		0.27
Mutation Taster		=79/21	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: rs55977045; hg19: chr2-179404197;