rs56207956

Variant names:

• chr2-178530340-C-G
• rs56207956
• NM_001267550.2:c.106275G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178530340-C-G
• chr2-178530340-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.106275G>C​(p.Gly35425Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0798 in 1,613,868 control chromosomes in the GnomAD database, including 5,714 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (475 hom., cov: 32)
  • Exomes 𝑓: 0.080 (5239 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: -0.159
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 2-178530340-C-G is Benign according to our data. Variant chr2-178530340-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.159 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0894 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.106275G>C	p.Gly35425Gly	synonymous	Exon 358 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.101352G>C	p.Gly33784Gly	synonymous	Exon 308 of 313	NP_001243779.1
	TTN	NM_133378.4		c.98571G>C	p.Gly32857Gly	synonymous	Exon 307 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.106275G>C	p.Gly35425Gly	synonymous	Exon 358 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.106119G>C	p.Gly35373Gly	synonymous	Exon 356 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.105999G>C	p.Gly35333Gly	synonymous	Exon 356 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0753 AC: 11459 AN: 152100 Hom.: 476 Cov.: 32

Gnomad AFR AF: 0.0727

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.0654

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.0717

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0913

Gnomad OTH AF: 0.0707

GnomAD2 exomes AF: 0.0645 AC: 16080 AN: 249134 AF XY: 0.0639

Gnomad AFR exome AF: 0.0732

Gnomad AMR exome AF: 0.0469

Gnomad ASJ exome AF: 0.0559

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0722

Gnomad NFE exome AF: 0.0888

Gnomad OTH exome AF: 0.0731

GnomAD4 exome AF: 0.0802 AC: 117274 AN: 1461650 Hom.: 5239 Cov.: 33 AF XY: 0.0787 AC XY: 57257 AN XY: 727106

African (AFR) AF: 0.0731 AC: 2447 AN: 33474

American (AMR) AF: 0.0491 AC: 2195 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0533 AC: 1393 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39694

South Asian (SAS) AF: 0.0259 AC: 2234 AN: 86258

European-Finnish (FIN) AF: 0.0735 AC: 3924 AN: 53384

Middle Eastern (MID) AF: 0.0700 AC: 404 AN: 5768

European-Non Finnish (NFE) AF: 0.0902 AC: 100273 AN: 1111842

Other (OTH) AF: 0.0729 AC: 4400 AN: 60374

GnomAD4 genome AF: 0.0753 AC: 11459 AN: 152218 Hom.: 475 Cov.: 32 AF XY: 0.0731 AC XY: 5443 AN XY: 74416

African (AFR) AF: 0.0726 AC: 3016 AN: 41530

American (AMR) AF: 0.0653 AC: 998 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 184 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0226 AC: 109 AN: 4820

European-Finnish (FIN) AF: 0.0717 AC: 760 AN: 10594

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0913 AC: 6207 AN: 68012

Other (OTH) AF: 0.0700 AC: 148 AN: 2114

Alfa AF: 0.0842 Hom.: 186

Bravo AF: 0.0744

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.0914

EpiControl AF: 0.0868

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.058
DANN	Benign	0.77
PhyloP100		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=80/20	polymorphism (auto)

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: rs56207956; hg19: chr2-179395067;