chr2-26477712-G-T

Variant names:

• chr2-26477712-G-T
• NM_194248.3:c.2252C>A

Variant summary

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

The NM_194248.3(OTOF):​c.2252C>A​(p.Thr751Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,426 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.92

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_194248.3	c.2252C>A	p.Thr751Lys	missense_variant	Exon 19 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.11C>A	p.Thr4Lys	missense_variant	Exon 2 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2252C>A	p.Thr751Lys	missense_variant	Exon 19 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.11C>A	p.Thr4Lys	missense_variant	Exon 2 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460426 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726504

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.12	.;.;.;T;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D
MetaSVM	Uncertain	0.029	D
MutationAssessor	Benign	1.9	.;.;.;L;L;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.7	D;D;.;N;N;.
REVEL	Uncertain	0.54
Sift	Benign	0.082	T;T;.;T;T;.
Sift4G	Benign	0.13	T;T;.;T;T;.
Polyphen		0.94	P;P;.;P;.;D
Vest4		0.77
MutPred		0.40		.;.;.;Gain of solvent accessibility (P = 0.0044);Gain of solvent accessibility (P = 0.0044);.;
MVP		0.92
MPC		0.34
ClinPred		0.93	D
GERP RS		4.8
Varity_R		0.35
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-26700580;