rs55696153

Variant names:

• chr2-178569410-A-G
• rs55696153
• NM_001267550.2:c.76722T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178569410-A-G
• chr2-178569410-A-T
• chr2-178569410-A-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001267550.2(TTN):​c.76722T>C​(p.Tyr25574Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,613,300 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (13 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:19
• Conservation: PhyloP100: 2.19
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-178569410-A-G is Benign according to our data. Variant chr2-178569410-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47350.
• BP7: Synonymous conserved (PhyloP=2.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00214 (325/152168) while in subpopulation NFE AF = 0.0039 (265/67992). AF 95% confidence interval is 0.00351. There are 0 homozygotes in GnomAd4. There are 122 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 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.76722T>C	p.Tyr25574Tyr	synonymous	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.71799T>C	p.Tyr23933Tyr	synonymous	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.69018T>C	p.Tyr23006Tyr	synonymous	Exon 275 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.76722T>C	p.Tyr25574Tyr	synonymous	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.76566T>C	p.Tyr25522Tyr	synonymous	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.76446T>C	p.Tyr25482Tyr	synonymous	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 325 AN: 152050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00390

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00210 AC: 520 AN: 247982 AF XY: 0.00204

Gnomad AFR exome AF: 0.000840

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.00406

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.00342 AC: 5001 AN: 1461132 Hom.: 13 Cov.: 41 AF XY: 0.00334 AC XY: 2426 AN XY: 726852

African (AFR) AF: 0.000508 AC: 17 AN: 33446

American (AMR) AF: 0.000380 AC: 17 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 51 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86196

European-Finnish (FIN) AF: 0.000599 AC: 32 AN: 53386

Middle Eastern (MID) AF: 0.00469 AC: 27 AN: 5758

European-Non Finnish (NFE) AF: 0.00419 AC: 4659 AN: 1111586

Other (OTH) AF: 0.00292 AC: 176 AN: 60346

GnomAD4 genome AF: 0.00214 AC: 325 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74378

African (AFR) AF: 0.000770 AC: 32 AN: 41538

American (AMR) AF: 0.000656 AC: 10 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00390 AC: 265 AN: 67992

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00287 Hom.: 2

Bravo AF: 0.00215

EpiCase AF: 0.00377

EpiControl AF: 0.00320

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	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	-0.52
CADD	Benign	0.033
DANN	Benign	0.69
PhyloP100		2.2
Mutation Taster		=82/18	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: rs55696153; hg19: chr2-179434137;