2-26479356-G-C

Variant names:

• chr2-26479356-G-C
• NM_194248.3:c.2122C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_194248.3(OTOF):​c.2122C>G​(p.Arg708Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34832236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2122C>G	p.Arg708Gly	missense_variant	Exon 18 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.2122C>G	p.Arg708Gly	missense_variant	Exon 18 of 46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2122C>G	p.Arg708Gly	missense_variant	Exon 18 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.2122C>G	p.Arg708Gly	missense_variant	Exon 18 of 46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.30
Sift	Benign	0.14	T;T
Sift4G	Benign	0.090	T;T
Polyphen		0.014	B;.
Vest4		0.42
MutPred		0.47		Loss of solvent accessibility (P = 0.0017);Loss of solvent accessibility (P = 0.0017);
MVP		0.82
MPC		0.21
ClinPred		0.79	D
GERP RS		2.6
Varity_R		0.27
gMVP		0.42

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-26702224;