rs10497517

Variant names:

• chr2-178578813-A-G
• rs10497517
• NM_001267550.2:c.68217T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.68217T>C​(p.His22739His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0577 in 1,609,840 control chromosomes in the GnomAD database, including 5,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (1227 hom., cov: 32)
  • Exomes 𝑓: 0.053 (4153 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 3.12
• Publications: 13 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]

ENSG00000270574 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 2-178578813-A-G is Benign according to our data. Variant chr2-178578813-A-G is described in ClinVar as Benign. ClinVar VariationId is 47263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 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.68217T>C	p.His22739His	synonymous	Exon 320 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.63294T>C	p.His21098His	synonymous	Exon 270 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.60513T>C	p.His20171His	synonymous	Exon 269 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.68217T>C	p.His22739His	synonymous	Exon 320 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.68061T>C	p.His22687His	synonymous	Exon 318 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.67941T>C	p.His22647His	synonymous	Exon 318 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0986 AC: 14984 AN: 151914 Hom.: 1206 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.0495

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.0248

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.0587

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0335

Gnomad OTH AF: 0.0810

GnomAD2 exomes AF: 0.0897 AC: 22134 AN: 246700 AF XY: 0.0862

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.0354

Gnomad EAS exome AF: 0.0276

Gnomad FIN exome AF: 0.0579

Gnomad NFE exome AF: 0.0354

Gnomad OTH exome AF: 0.0703

GnomAD4 exome AF: 0.0534 AC: 77894 AN: 1457808 Hom.: 4153 Cov.: 33 AF XY: 0.0555 AC XY: 40254 AN XY: 724676

African (AFR) AF: 0.205 AC: 6835 AN: 33266

American (AMR) AF: 0.205 AC: 9101 AN: 44322

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 945 AN: 26050

East Asian (EAS) AF: 0.0138 AC: 547 AN: 39592

South Asian (SAS) AF: 0.174 AC: 14934 AN: 85588

European-Finnish (FIN) AF: 0.0593 AC: 3163 AN: 53362

Middle Eastern (MID) AF: 0.0589 AC: 338 AN: 5734

European-Non Finnish (NFE) AF: 0.0344 AC: 38188 AN: 1109688

Other (OTH) AF: 0.0638 AC: 3843 AN: 60206

GnomAD4 genome AF: 0.0990 AC: 15057 AN: 152032 Hom.: 1227 Cov.: 32 AF XY: 0.105 AC XY: 7798 AN XY: 74306

African (AFR) AF: 0.197 AC: 8150 AN: 41466

American (AMR) AF: 0.175 AC: 2665 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 126 AN: 3468

East Asian (EAS) AF: 0.0250 AC: 129 AN: 5150

South Asian (SAS) AF: 0.176 AC: 850 AN: 4816

European-Finnish (FIN) AF: 0.0587 AC: 622 AN: 10602

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0335 AC: 2277 AN: 67960

Other (OTH) AF: 0.0802 AC: 169 AN: 2108

Alfa AF: 0.0605 Hom.: 991

Bravo AF: 0.108

Asia WGS AF: 0.127 AC: 440 AN: 3474

EpiCase AF: 0.0332

EpiControl AF: 0.0342

ClinVar

ClinVar submissions

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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.67
PhyloP100		3.1
Mutation Taster		=80/20	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: rs10497517; hg19: chr2-179443540;