2-26477231-G-C

Variant names:

• chr2-26477231-G-C
• rs80356570
• NM_194248.3:c.2464C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_194248.3(OTOF):​c.2464C>G​(p.Arg822Gly) 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. R822Q) has been classified as Likely benign. The gene OTOF is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12
• Publications: 0 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, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for OTOF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194248.3. 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
	OTOF	NM_194248.3	MANE Select	c.2464C>G	p.Arg822Gly	missense	Exon 21 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.223C>G	p.Arg75Gly	missense	Exon 4 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.2464C>G	p.Arg822Gly	missense	Exon 21 of 46	NP_001274418.1	Q9HC10-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.2464C>G	p.Arg822Gly	missense	Exon 21 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.223C>G	p.Arg75Gly	missense	Exon 4 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.223C>G	p.Arg75Gly	missense	Exon 3 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.029
Eigen_PC	Benign	0.023
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.023	D
Polyphen		0.42	B
Vest4		0.27
MutPred		0.44		Gain of helix (P = 0.0496)
MVP		0.87
MPC		0.29
ClinPred		0.98	D
GERP RS		2.9
Varity_R		0.31
gMVP		0.46
Mutation Taster		=92/8	polymorphism

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: rs80356570; hg19: chr2-26700099;