rs11694623

Variant names:

• chr2-178548725-G-A
• rs11694623
• NM_001267550.2:c.92901C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178548725-G-A
• chr2-178548725-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.92901C>T​(p.Ser30967Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 1,613,798 control chromosomes in the GnomAD database, including 601 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (39 hom., cov: 33)
  • Exomes 𝑓: 0.026 (562 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 0.564
• Publications: 4 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]

ENSG00000270277 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-178548725-G-A is Benign according to our data. Variant chr2-178548725-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.564 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0197 (2998/152284) while in subpopulation AMR AF = 0.033 (505/15292). AF 95% confidence interval is 0.0306. There are 39 homozygotes in GnomAd4. There are 1361 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 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.92901C>T	p.Ser30967Ser	synonymous	Exon 339 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.87978C>T	p.Ser29326Ser	synonymous	Exon 289 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.85197C>T	p.Ser28399Ser	synonymous	Exon 288 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.92901C>T	p.Ser30967Ser	synonymous	Exon 339 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.92745C>T	p.Ser30915Ser	synonymous	Exon 337 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.92625C>T	p.Ser30875Ser	synonymous	Exon 337 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2999 AN: 152166 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.00606

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00558

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0296

Gnomad OTH AF: 0.0321

GnomAD2 exomes AF: 0.0197 AC: 4907 AN: 248876 AF XY: 0.0202

Gnomad AFR exome AF: 0.00491

Gnomad AMR exome AF: 0.0230

Gnomad ASJ exome AF: 0.0233

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00488

Gnomad NFE exome AF: 0.0296

Gnomad OTH exome AF: 0.0334

GnomAD4 exome AF: 0.0256 AC: 37428 AN: 1461514 Hom.: 562 Cov.: 35 AF XY: 0.0252 AC XY: 18350 AN XY: 727054

African (AFR) AF: 0.00490 AC: 164 AN: 33470

American (AMR) AF: 0.0237 AC: 1062 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 647 AN: 26130

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39694

South Asian (SAS) AF: 0.00547 AC: 472 AN: 86258

European-Finnish (FIN) AF: 0.00577 AC: 308 AN: 53334

Middle Eastern (MID) AF: 0.0163 AC: 94 AN: 5768

European-Non Finnish (NFE) AF: 0.0299 AC: 33250 AN: 1111780

Other (OTH) AF: 0.0236 AC: 1426 AN: 60364

GnomAD4 genome AF: 0.0197 AC: 2998 AN: 152284 Hom.: 39 Cov.: 33 AF XY: 0.0183 AC XY: 1361 AN XY: 74458

African (AFR) AF: 0.00604 AC: 251 AN: 41574

American (AMR) AF: 0.0330 AC: 505 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 81 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00559 AC: 27 AN: 4832

European-Finnish (FIN) AF: 0.00396 AC: 42 AN: 10608

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0296 AC: 2013 AN: 68012

Other (OTH) AF: 0.0317 AC: 67 AN: 2112

Alfa AF: 0.0251 Hom.: 138

Bravo AF: 0.0213

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.0317

EpiControl AF: 0.0318

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	5	not provided (5)
-	-	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	-0.45
CADD	Benign	0.17
DANN	Benign	0.80
PhyloP100		0.56
Mutation Taster		=95/5	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: rs11694623; hg19: chr2-179413452;