NM_001267550.2:c.26765G>A

Variant names:

• chr2-178713369-C-T
• rs397517520
• NM_001267550.2:c.26765G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001267550.2(TTN):​c.26765G>A​(p.Arg8922Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,502,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.94
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23143265).
• BP6: Variant 2-178713369-C-T is Benign according to our data. Variant chr2-178713369-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46790.

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.26765G>A	p.Arg8922Gln	missense	Exon 93 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.25814G>A	p.Arg8605Gln	missense	Exon 91 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.23033G>A	p.Arg7678Gln	missense	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.26765G>A	p.Arg8922Gln	missense	Exon 93 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.26765G>A	p.Arg8922Gln	missense	Exon 93 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.26489G>A	p.Arg8830Gln	missense	Exon 91 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0000208 AC: 3 AN: 143978 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000753

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000292 AC: 4 AN: 136820 AF XY: 0.0000560

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 28 AN: 1358112 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 18 AN XY: 667236

African (AFR) AF: 0.000164 AC: 5 AN: 30538

American (AMR) AF: 0.00 AC: 0 AN: 31446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23420

East Asian (EAS) AF: 0.0000675 AC: 2 AN: 29612

South Asian (SAS) AF: 0.000228 AC: 17 AN: 74526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47426

Middle Eastern (MID) AF: 0.000214 AC: 1 AN: 4674

European-Non Finnish (NFE) AF: 0.00000283 AC: 3 AN: 1060514

Other (OTH) AF: 0.00 AC: 0 AN: 55956

GnomAD4 genome AF: 0.0000208 AC: 3 AN: 143978 Hom.: 0 Cov.: 32 AF XY: 0.0000143 AC XY: 1 AN XY: 70050

African (AFR) AF: 0.0000753 AC: 3 AN: 39834

American (AMR) AF: 0.00 AC: 0 AN: 14350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3298

East Asian (EAS) AF: 0.00 AC: 0 AN: 3560

South Asian (SAS) AF: 0.00 AC: 0 AN: 4590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65488

Other (OTH) AF: 0.00 AC: 0 AN: 1996

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	not specified (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.86
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.84	T
PhyloP100		2.9
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.24
Sift	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.32
MutPred		0.26		Loss of phosphorylation at S8603 (P = 0.101)
MVP		0.13
MPC		0.38
ClinPred		0.12	T
GERP RS		6.2
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs397517520; hg19: chr2-179578096;