rs56324602

Variant names:

• chr2-178529113-C-T
• rs56324602
• NM_001267550.2:c.106638G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178529113-C-T
• chr2-178529113-C-A
• chr2-178529113-C-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.106638G>A​(p.Arg35546Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,594,198 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (47 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:28
• Conservation: PhyloP100: 0.823
• Publications: 1 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=-0.48).
• BP6: Variant 2-178529113-C-T is Benign according to our data. Variant chr2-178529113-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.823 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00176 (268/152228) while in subpopulation SAS AF = 0.024 (116/4826). AF 95% confidence interval is 0.0205. There are 5 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.106638G>A	p.Arg35546Arg	synonymous	Exon 360 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.101715G>A	p.Arg33905Arg	synonymous	Exon 310 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.98934G>A	p.Arg32978Arg	synonymous	Exon 309 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.106638G>A	p.Arg35546Arg	synonymous	Exon 360 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.106482G>A	p.Arg35494Arg	synonymous	Exon 358 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.106362G>A	p.Arg35454Arg	synonymous	Exon 358 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 265 AN: 152110 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00381 AC: 901 AN: 236276 AF XY: 0.00486

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.000857

Gnomad ASJ exome AF: 0.000971

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00221 AC: 3182 AN: 1441970 Hom.: 47 Cov.: 32 AF XY: 0.00283 AC XY: 2027 AN XY: 715628

African (AFR) AF: 0.000342 AC: 11 AN: 32150

American (AMR) AF: 0.000761 AC: 31 AN: 40750

Ashkenazi Jewish (ASJ) AF: 0.000868 AC: 22 AN: 25340

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39486

South Asian (SAS) AF: 0.0217 AC: 1793 AN: 82766

European-Finnish (FIN) AF: 0.0000760 AC: 4 AN: 52664

Middle Eastern (MID) AF: 0.00442 AC: 25 AN: 5654

European-Non Finnish (NFE) AF: 0.00102 AC: 1130 AN: 1103790

Other (OTH) AF: 0.00276 AC: 164 AN: 59370

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152228 Hom.: 5 Cov.: 33 AF XY: 0.00203 AC XY: 151 AN XY: 74428

African (AFR) AF: 0.000169 AC: 7 AN: 41538

American (AMR) AF: 0.00170 AC: 26 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0240 AC: 116 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.00166 AC: 113 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.00104

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	6	not provided (6)
-	-	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	-0.48
CADD	Benign	0.045
DANN	Benign	0.51
PhyloP100		0.82
Mutation Taster		=100/0	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: rs56324602; hg19: chr2-179393840;