2-26458055-C-G

Variant names:

• chr2-26458055-C-G
• rs765372800
• NM_194323.3:c.3678G>C

Variant summary

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

The NM_194323.3(OTOF):​c.3678G>C​(p.Lys1226Asn) 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.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OTOF NM_194323.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.34

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 rank	MANE	Protein	UniProt
OTOF	NM_194323.3	c.3678G>C	p.Lys1226Asn	missense_variant	Exon 29 of 29	ENST00000339598.8	NP_919304.1
OTOF	NM_194248.3	c.*183G>C		3_prime_UTR_variant	Exon 47 of 47	ENST00000272371.7	NP_919224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000339598.8	c.3678G>C	p.Lys1226Asn	missense_variant	Exon 29 of 29	1	NM_194323.3	ENSP00000344521.3
OTOF	ENST00000272371	c.*183G>C		3_prime_UTR_variant	Exon 47 of 47	1	NM_194248.3	ENSP00000272371.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250658 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135432

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Uncertain	0.62	D
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.58
MutPred		0.21		Loss of methylation at K1226 (P = 0.0032);.;
MVP		0.95
ClinPred		0.57	D
GERP RS		4.8

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: rs765372800; hg19: chr2-26680923;