chr2-26477633-G-A

Variant names:

• chr2-26477633-G-A
• rs73920286
• NM_194248.3:c.2315+16C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_194248.3(OTOF):​c.2315+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00682 in 1,611,668 control chromosomes in the GnomAD database, including 530 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (275 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (255 hom.)
• Consequence: OTOF NM_194248.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.59
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-26477633-G-A is Benign according to our data. Variant chr2-26477633-G-A is described in ClinVar as Benign. ClinVar VariationId is 263081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	NM_194248.3	MANE Select	c.2315+16C>T		intron	N/A	NP_919224.1
	OTOF	NM_194323.3	MANE Plus Clinical	c.74+16C>T		intron	N/A	NP_919304.1
	OTOF	NM_001287489.2		c.2315+16C>T		intron	N/A	NP_001274418.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.2315+16C>T		intron	N/A	ENSP00000272371.2
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.74+16C>T		intron	N/A	ENSP00000344521.3
	OTOF	ENST00000402415.8	TSL:1	c.74+16C>T		intron	N/A	ENSP00000383906.4

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5145 AN: 151976 Hom.: 274 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.0240

GnomAD2 exomes AF: 0.00913 AC: 2250 AN: 246546 AF XY: 0.00688

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.00578

Gnomad ASJ exome AF: 0.00222

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000473

Gnomad NFE exome AF: 0.000741

Gnomad OTH exome AF: 0.00431

GnomAD4 exome AF: 0.00400 AC: 5831 AN: 1459574 Hom.: 255 Cov.: 34 AF XY: 0.00351 AC XY: 2549 AN XY: 726106

African (AFR) AF: 0.120 AC: 4008 AN: 33462

American (AMR) AF: 0.00664 AC: 297 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00191 AC: 50 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00273 AC: 235 AN: 86224

European-Finnish (FIN) AF: 0.0000388 AC: 2 AN: 51516

Middle Eastern (MID) AF: 0.00884 AC: 51 AN: 5766

European-Non Finnish (NFE) AF: 0.000607 AC: 675 AN: 1111738

Other (OTH) AF: 0.00850 AC: 513 AN: 60332

GnomAD4 genome AF: 0.0340 AC: 5166 AN: 152094 Hom.: 275 Cov.: 32 AF XY: 0.0326 AC XY: 2424 AN XY: 74350

African (AFR) AF: 0.116 AC: 4823 AN: 41464

American (AMR) AF: 0.0148 AC: 226 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5156

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 67968

Other (OTH) AF: 0.0237 AC: 50 AN: 2108

Alfa AF: 0.0168 Hom.: 18

Bravo AF: 0.0385

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.43
DANN	Benign	0.69
PhyloP100		-1.6
PromoterAI		-0.022	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs73920286; hg19: chr2-26700501;