2-26460203-C-G

Variant names:

• chr2-26460203-C-G
• rs80356605
• NM_194248.3:c.5816G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_194248.3(OTOF):​c.5816G>C​(p.Arg1939Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,342 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. R1939W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: OTOF NM_194248.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.63
• Publications: 36 publications found

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]

OTOF Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-26460204-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 65813.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.5816G>C	p.Arg1939Pro	missense_variant, splice_region_variant	Exon 46 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.3512+444G>C		intron_variant	Intron 28 of 28	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.5816G>C	p.Arg1939Pro	missense_variant, splice_region_variant	Exon 46 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.3512+444G>C		intron_variant	Intron 28 of 28	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000437 AC: 1 AN: 228634 AF XY: 0.00000814

Gnomad AFR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448342 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 719068

African (AFR) AF: 0.00 AC: 0 AN: 33248

American (AMR) AF: 0.00 AC: 0 AN: 43040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25914

East Asian (EAS) AF: 0.00 AC: 0 AN: 39326

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4290

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106120

Other (OTH) AF: 0.00 AC: 0 AN: 59864

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;.;D;.
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.6	.;.;H;.
PhyloP100		2.6
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-6.7	D;.;D;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0050	D;.;D;.
Sift4G	Pathogenic	0.0	D;.;D;.
Polyphen		1.0	D;.;D;D
Vest4		0.65
MutPred		0.55		.;.;Gain of catalytic residue at R1939 (P = 0.0047);.;
MVP		0.91
MPC		0.77
ClinPred		0.99	D
GERP RS		2.3
Varity_R		0.97
gMVP		0.97
Mutation Taster		=25/75	disease causing

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: rs80356605; hg19: chr2-26683071;