rs878854300

Variant names:

• chr2-178662773-G-A
• rs878854300
• NM_001267550.2:c.36830C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178662773-G-A
• chr2-178662773-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001267550.2(TTN):​c.36830C>T​(p.Ala12277Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 20)
  • Exomes 𝑓: 0.000084 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.638
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015921652).
• BP6: Variant 2-178662773-G-A is Benign according to our data. Variant chr2-178662773-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 238755.Status of the report is criteria_provided_single_submitter, 1 stars.

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.36830C>T	p.Ala12277Val	missense	Exon 175 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34354+193C>T		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31573+193C>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.36830C>T	p.Ala12277Val	missense	Exon 175 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.36830C>T	p.Ala12277Val	missense	Exon 175 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.36554C>T	p.Ala12185Val	missense	Exon 173 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 16 AN: 134780 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.000282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000152

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000636

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000519 AC: 29 AN: 55920 AF XY: 0.000713

Gnomad AFR exome AF: 0.000568

Gnomad AMR exome AF: 0.000557

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000127

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000138

Gnomad OTH exome AF: 0.00103

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000837 AC: 102 AN: 1218788 Hom.: 0 Cov.: 17 AF XY: 0.000103 AC XY: 63 AN XY: 609500

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000252 AC: 7 AN: 27820

American (AMR) AF: 0.000166 AC: 6 AN: 36136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21694

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37466

South Asian (SAS) AF: 0.000775 AC: 58 AN: 74812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39490

Middle Eastern (MID) AF: 0.000853 AC: 3 AN: 3516

European-Non Finnish (NFE) AF: 0.0000248 AC: 23 AN: 926268

Other (OTH) AF: 0.0000775 AC: 4 AN: 51586

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000119 AC: 16 AN: 134866 Hom.: 0 Cov.: 20 AF XY: 0.0000927 AC XY: 6 AN XY: 64702

African (AFR) AF: 0.000281 AC: 10 AN: 35590

American (AMR) AF: 0.000152 AC: 2 AN: 13194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3250

East Asian (EAS) AF: 0.00 AC: 0 AN: 4480

South Asian (SAS) AF: 0.00 AC: 0 AN: 3814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.0000636 AC: 4 AN: 62898

Other (OTH) AF: 0.00 AC: 0 AN: 1768

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.6
DANN	Benign	0.72
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.00091	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.64
Vest4		0.030
MVP		0.25
MPC		0.083
ClinPred		0.0058	T
GERP RS		3.3
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs878854300; hg19: chr2-179527500;