rs61232800

Variant names:

• chr2-178713143-T-C
• rs61232800
• NM_001267550.2:c.26991A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178713143-T-C
• chr2-178713143-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.26991A>G​(p.Thr8997Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00459 in 1,613,814 control chromosomes in the GnomAD database, including 232 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. T8997T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (115 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (117 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: -6.35
• Publications: 1 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 (BayesDel_noAF=-0.93).
• BP6: Variant 2-178713143-T-C is Benign according to our data. Variant chr2-178713143-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0728 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.26991A>G	p.Thr8997Thr	synonymous	Exon 93 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.26040A>G	p.Thr8680Thr	synonymous	Exon 91 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.23259A>G	p.Thr7753Thr	synonymous	Exon 90 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.26991A>G	p.Thr8997Thr	synonymous	Exon 93 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.26991A>G	p.Thr8997Thr	synonymous	Exon 93 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.26715A>G	p.Thr8905Thr	synonymous	Exon 91 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3346 AN: 152198 Hom.: 115 Cov.: 33

Gnomad AFR AF: 0.0749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.00619 AC: 1540 AN: 248802 AF XY: 0.00498

Gnomad AFR exome AF: 0.0741

Gnomad AMR exome AF: 0.00363

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000541

Gnomad OTH exome AF: 0.00448

GnomAD4 exome AF: 0.00277 AC: 4052 AN: 1461498 Hom.: 117 Cov.: 32 AF XY: 0.00249 AC XY: 1808 AN XY: 727020

African (AFR) AF: 0.0805 AC: 2695 AN: 33468

American (AMR) AF: 0.00414 AC: 185 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0169 AC: 442 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000487 AC: 42 AN: 86244

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53386

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5766

European-Non Finnish (NFE) AF: 0.000242 AC: 269 AN: 1111752

Other (OTH) AF: 0.00623 AC: 376 AN: 60366

GnomAD4 genome AF: 0.0221 AC: 3360 AN: 152316 Hom.: 115 Cov.: 33 AF XY: 0.0214 AC XY: 1595 AN XY: 74484

African (AFR) AF: 0.0750 AC: 3119 AN: 41570

American (AMR) AF: 0.00680 AC: 104 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68028

Other (OTH) AF: 0.0232 AC: 49 AN: 2116

Alfa AF: 0.00937 Hom.: 34

Bravo AF: 0.0258

EpiCase AF: 0.000764

EpiControl AF: 0.000949

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy (1)
-	-	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)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.012
DANN	Benign	0.54
PhyloP100		-6.4
Mutation Taster		=82/18	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: rs61232800; hg19: chr2-179577870;