2-26477243-G-C

Position:

• chr2-26477243-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000272371.7(OTOF):​c.2452C>G​(p.Arg818Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R818Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOF ENST00000272371.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.41

Genes affected

OTOF (HGNC:8515): (otoferlin) Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has 3 C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has 6 C2 domains. The homology suggests that this protein may be involved in vesicle membrane fusion. Several transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2452C>G	p.Arg818Gly	missense_variant	21/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.211C>G	p.Arg71Gly	missense_variant	4/29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2452C>G	p.Arg818Gly	missense_variant	21/47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.211C>G	p.Arg71Gly	missense_variant	4/29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;.;.;T;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.044
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.42	T;T;T;T;T;T
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Benign	1.9	.;.;.;L;L;.
MutationTaster	Benign	0.85	D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0060	D;D;D;D;D;.
Sift4G	Uncertain	0.020	D;D;.;D;D;.
Polyphen		0.64	P;B;.;B;.;B
Vest4		0.42
MutPred		0.41		.;.;.;Loss of stability (P = 0.0304);Loss of stability (P = 0.0304);.;
MVP		0.86
MPC		0.21
ClinPred		0.98	D
GERP RS		1.5
Varity_R		0.39
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs2272070; hg19: chr2-26700111;