NM_194248.3:c.2512C>T

Variant names:

• chr2-26477183-G-A
• rs146139327
• NM_194248.3:c.2512C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_194248.3(OTOF):​c.2512C>T​(p.Leu838Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00042 in 1,610,588 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (7 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.85
• Publications: 2 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-26477183-G-A is Benign according to our data. Variant chr2-26477183-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48200.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00025 (38/152304) while in subpopulation SAS AF = 0.00435 (21/4828). AF 95% confidence interval is 0.00291. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

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.2512C>T	p.Leu838Leu	synonymous	Exon 21 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.271C>T	p.Leu91Leu	synonymous	Exon 4 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.2512C>T	p.Leu838Leu	synonymous	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.2512C>T	p.Leu838Leu	synonymous	Exon 21 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.271C>T	p.Leu91Leu	synonymous	Exon 4 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.271C>T	p.Leu91Leu	synonymous	Exon 3 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000721 AC: 176 AN: 244162 AF XY: 0.00105

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000172

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000438 AC: 639 AN: 1458284 Hom.: 7 Cov.: 33 AF XY: 0.000616 AC XY: 447 AN XY: 725352

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.000314 AC: 14 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00517 AC: 444 AN: 85924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50878

Middle Eastern (MID) AF: 0.00263 AC: 15 AN: 5700

European-Non Finnish (NFE) AF: 0.000126 AC: 140 AN: 1111618

Other (OTH) AF: 0.000414 AC: 25 AN: 60320

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74466

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000174

EpiCase AF: 0.000600

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 9 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		3.9
Mutation Taster		=96/4	polymorphism

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: rs146139327; hg19: chr2-26700051;