rs201184203

Variant names:

• chr2-178664094-G-A
• rs201184203
• NM_001267550.2:c.36285C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178664094-G-A
• chr2-178664094-G-T
• chr2-178664094-G-C

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.36285C>T​(p.His12095His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,608,628 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.466
• Publications: 0 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.012).
• BP6: Variant 2-178664094-G-A is Benign according to our data. Variant chr2-178664094-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.466 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00139 (211/151406) while in subpopulation SAS AF = 0.00443 (21/4736). AF 95% confidence interval is 0.00297. There are 0 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.36285C>T	p.His12095His	synonymous	Exon 169 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34265-1039C>T		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31484-1039C>T		intron	N/A	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.36285C>T	p.His12095His	synonymous	Exon 169 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.36285C>T	p.His12095His	synonymous	Exon 169 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.36009C>T	p.His12003His	synonymous	Exon 167 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 151286 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000365

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00443

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.000962

GnomAD2 exomes AF: 0.00131 AC: 313 AN: 239722 AF XY: 0.00141

Gnomad AFR exome AF: 0.000209

Gnomad AMR exome AF: 0.000419

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.0000571

Gnomad FIN exome AF: 0.000281

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.000343

GnomAD4 exome AF: 0.00188 AC: 2734 AN: 1457222 Hom.: 3 Cov.: 33 AF XY: 0.00191 AC XY: 1388 AN XY: 724972

African (AFR) AF: 0.000242 AC: 8 AN: 33084

American (AMR) AF: 0.000412 AC: 18 AN: 43734

Ashkenazi Jewish (ASJ) AF: 0.000232 AC: 6 AN: 25888

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00235 AC: 201 AN: 85552

European-Finnish (FIN) AF: 0.000303 AC: 16 AN: 52764

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5736

European-Non Finnish (NFE) AF: 0.00216 AC: 2398 AN: 1110656

Other (OTH) AF: 0.00140 AC: 84 AN: 60126

GnomAD4 genome AF: 0.00139 AC: 211 AN: 151406 Hom.: 0 Cov.: 31 AF XY: 0.00133 AC XY: 98 AN XY: 73946

African (AFR) AF: 0.000364 AC: 15 AN: 41204

American (AMR) AF: 0.000263 AC: 4 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00443 AC: 21 AN: 4736

European-Finnish (FIN) AF: 0.000284 AC: 3 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00243 AC: 165 AN: 67832

Other (OTH) AF: 0.000952 AC: 2 AN: 2100

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00125

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00197

EpiControl AF: 0.00178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	5	not specified (5)
-	-	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	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	-0.83
CADD	Benign	0.088
DANN	Benign	0.81
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs201184203; hg19: chr2-179528821;