rs55972010

Variant names:

• chr2-178559321-T-C
• rs55972010
• NM_001267550.2:c.86811A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178559321-T-C
• chr2-178559321-T-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.86811A>G​(p.Val28937Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,589,816 control chromosomes in the GnomAD database, including 703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V28937V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (36 hom., cov: 33)
  • Exomes 𝑓: 0.028 (667 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 0.0260
• Publications: 5 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=-0.56).
• BP6: Variant 2-178559321-T-C is Benign according to our data. Variant chr2-178559321-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.026 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0203 (3097/152324) while in subpopulation NFE AF = 0.0311 (2117/68028). AF 95% confidence interval is 0.03. There are 36 homozygotes in GnomAd4. There are 1509 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 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.86811A>G	p.Val28937Val	synonymous	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.81888A>G	p.Val27296Val	synonymous	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.79107A>G	p.Val26369Val	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.86811A>G	p.Val28937Val	synonymous	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.86655A>G	p.Val28885Val	synonymous	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.86535A>G	p.Val28845Val	synonymous	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3096 AN: 152206 Hom.: 36 Cov.: 33

Gnomad AFR AF: 0.00427

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0311

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0228 AC: 5349 AN: 234150 AF XY: 0.0243

Gnomad AFR exome AF: 0.00415

Gnomad AMR exome AF: 0.00956

Gnomad ASJ exome AF: 0.0247

Gnomad EAS exome AF: 0.0000578

Gnomad FIN exome AF: 0.0265

Gnomad NFE exome AF: 0.0313

Gnomad OTH exome AF: 0.0262

GnomAD4 exome AF: 0.0284 AC: 40762 AN: 1437492 Hom.: 667 Cov.: 31 AF XY: 0.0286 AC XY: 20411 AN XY: 712480

African (AFR) AF: 0.00335 AC: 108 AN: 32192

American (AMR) AF: 0.0104 AC: 428 AN: 41030

Ashkenazi Jewish (ASJ) AF: 0.0235 AC: 589 AN: 25080

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39412

South Asian (SAS) AF: 0.0251 AC: 2069 AN: 82360

European-Finnish (FIN) AF: 0.0279 AC: 1476 AN: 52892

Middle Eastern (MID) AF: 0.0241 AC: 136 AN: 5640

European-Non Finnish (NFE) AF: 0.0313 AC: 34470 AN: 1099616

Other (OTH) AF: 0.0251 AC: 1485 AN: 59270

GnomAD4 genome AF: 0.0203 AC: 3097 AN: 152324 Hom.: 36 Cov.: 33 AF XY: 0.0203 AC XY: 1509 AN XY: 74482

African (AFR) AF: 0.00426 AC: 177 AN: 41576

American (AMR) AF: 0.0158 AC: 242 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0273 AC: 132 AN: 4828

European-Finnish (FIN) AF: 0.0250 AC: 266 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0311 AC: 2117 AN: 68028

Other (OTH) AF: 0.0194 AC: 41 AN: 2116

Alfa AF: 0.0259 Hom.: 31

Bravo AF: 0.0182

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
-	-	11	not specified (11)
-	-	3	not provided (3)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.070
DANN	Benign	0.69
PhyloP100		0.026
Mutation Taster		=99/1	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: rs55972010; hg19: chr2-179424048;