rs10183237

Variant names:

• chr2-178715483-G-A
• rs10183237
• NM_001267550.2:c.25921+10C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178715483-G-A
• chr2-178715483-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.25921+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.047 in 1,604,038 control chromosomes in the GnomAD database, including 3,868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (771 hom., cov: 32)
  • Exomes 𝑓: 0.044 (3097 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.144
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-178715483-G-A is Benign according to our data. Variant chr2-178715483-G-A is described in ClinVar as Benign. ClinVar VariationId is 46769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.152 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.25921+10C>T		intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.24970+10C>T		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.22189+10C>T		intron	N/A	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.25921+10C>T		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.25921+10C>T		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.25645+10C>T		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0788 AC: 11979 AN: 151996 Hom.: 749 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.0261

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.0583

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0251

Gnomad OTH AF: 0.0676

GnomAD2 exomes AF: 0.0783 AC: 19108 AN: 244124 AF XY: 0.0757

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.0398

Gnomad EAS exome AF: 0.0282

Gnomad FIN exome AF: 0.0574

Gnomad NFE exome AF: 0.0262

Gnomad OTH exome AF: 0.0603

GnomAD4 exome AF: 0.0436 AC: 63343 AN: 1451924 Hom.: 3097 Cov.: 32 AF XY: 0.0458 AC XY: 33013 AN XY: 720762

African (AFR) AF: 0.157 AC: 5226 AN: 33190

American (AMR) AF: 0.187 AC: 8270 AN: 44248

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 1023 AN: 25676

East Asian (EAS) AF: 0.0134 AC: 531 AN: 39518

South Asian (SAS) AF: 0.159 AC: 13597 AN: 85494

European-Finnish (FIN) AF: 0.0589 AC: 3123 AN: 53056

Middle Eastern (MID) AF: 0.0415 AC: 237 AN: 5710

European-Non Finnish (NFE) AF: 0.0256 AC: 28245 AN: 1105146

Other (OTH) AF: 0.0516 AC: 3091 AN: 59886

GnomAD4 genome AF: 0.0792 AC: 12042 AN: 152114 Hom.: 771 Cov.: 32 AF XY: 0.0833 AC XY: 6197 AN XY: 74354

African (AFR) AF: 0.151 AC: 6266 AN: 41478

American (AMR) AF: 0.145 AC: 2221 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3470

East Asian (EAS) AF: 0.0263 AC: 136 AN: 5162

South Asian (SAS) AF: 0.162 AC: 776 AN: 4804

European-Finnish (FIN) AF: 0.0583 AC: 618 AN: 10596

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0251 AC: 1707 AN: 68012

Other (OTH) AF: 0.0669 AC: 141 AN: 2108

Alfa AF: 0.0477 Hom.: 535

Bravo AF: 0.0859

Asia WGS AF: 0.119 AC: 411 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	Dilated cardiomyopathy 1G (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.044
DANN	Benign	0.70
PhyloP100		0.14
Mutation Taster		=100/0	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: rs10183237; hg19: chr2-179580210;