chr2-26476258-C-G

Variant names:

• chr2-26476258-C-G
• rs4335905
• NM_194248.3:c.2736G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_194248.3(OTOF):​c.2736G>C​(p.Leu912Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 1,606,032 control chromosomes in the GnomAD database, including 205,642 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (26656 hom., cov: 33)
  • Exomes 𝑓: 0.48 (178986 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -1.32
• Publications: 25 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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-26476258-C-G is Benign according to our data. Variant chr2-26476258-C-G is described in ClinVar as Benign. ClinVar VariationId is 21839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	NM_194248.3	MANE Select	c.2736G>C	p.Leu912Leu	synonymous	Exon 23 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.495G>C	p.Leu165Leu	synonymous	Exon 6 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.2736G>C	p.Leu912Leu	synonymous	Exon 23 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.2736G>C	p.Leu912Leu	synonymous	Exon 23 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.495G>C	p.Leu165Leu	synonymous	Exon 6 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.495G>C	p.Leu165Leu	synonymous	Exon 5 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86904 AN: 151892 Hom.: 26613 Cov.: 33

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.527

GnomAD2 exomes AF: 0.569 AC: 137121 AN: 240986 AF XY: 0.554

Gnomad AFR exome AF: 0.727

Gnomad AMR exome AF: 0.732

Gnomad ASJ exome AF: 0.445

Gnomad EAS exome AF: 0.987

Gnomad FIN exome AF: 0.580

Gnomad NFE exome AF: 0.435

Gnomad OTH exome AF: 0.514

GnomAD4 exome AF: 0.483 AC: 701814 AN: 1454022 Hom.: 178986 Cov.: 56 AF XY: 0.483 AC XY: 349760 AN XY: 723610

African (AFR) AF: 0.725 AC: 24274 AN: 33460

American (AMR) AF: 0.718 AC: 32091 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 11763 AN: 26112

East Asian (EAS) AF: 0.977 AC: 38781 AN: 39690

South Asian (SAS) AF: 0.578 AC: 49877 AN: 86218

European-Finnish (FIN) AF: 0.574 AC: 26684 AN: 46520

Middle Eastern (MID) AF: 0.450 AC: 2431 AN: 5408

European-Non Finnish (NFE) AF: 0.436 AC: 484819 AN: 1111672

Other (OTH) AF: 0.516 AC: 31094 AN: 60258

GnomAD4 genome AF: 0.572 AC: 87012 AN: 152010 Hom.: 26656 Cov.: 33 AF XY: 0.581 AC XY: 43193 AN XY: 74286

African (AFR) AF: 0.724 AC: 30002 AN: 41454

American (AMR) AF: 0.633 AC: 9682 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1544 AN: 3470

East Asian (EAS) AF: 0.983 AC: 5063 AN: 5148

South Asian (SAS) AF: 0.592 AC: 2856 AN: 4824

European-Finnish (FIN) AF: 0.610 AC: 6470 AN: 10600

Middle Eastern (MID) AF: 0.384 AC: 112 AN: 292

European-Non Finnish (NFE) AF: 0.437 AC: 29646 AN: 67914

Other (OTH) AF: 0.532 AC: 1122 AN: 2110

Alfa AF: 0.468 Hom.: 5574

Bravo AF: 0.584

Asia WGS AF: 0.776 AC: 2695 AN: 3476

EpiCase AF: 0.441

EpiControl AF: 0.432

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Autosomal recessive nonsyndromic hearing loss 9 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.52
PhyloP100		-1.3
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4335905; hg19: chr2-26699126; COSMIC: COSV55500530; COSMIC: COSV55500530;