chr12-80358862-T-C

Variant names:

• chr12-80358862-T-C
• rs145929269
• NM_001378609.3:c.6229T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001378609.3(OTOGL):​c.6229T>C​(p.Cys2077Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. C2077G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOGL NM_001378609.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.71
• Publications: 2 publications found

Genes affected

OTOGL (HGNC:26901): (otogelin like) The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]

OTOGL Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 84B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378609.3. 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
	OTOGL	NM_001378609.3	MANE Select	c.6229T>C	p.Cys2077Arg	missense splice_region	Exon 52 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.6229T>C	p.Cys2077Arg	missense splice_region	Exon 55 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.6229T>C	p.Cys2077Arg	missense splice_region	Exon 52 of 59	NP_775862.4	Q3ZCN5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.6229T>C	p.Cys2077Arg	missense splice_region	Exon 52 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.6094T>C	p.Cys2032Arg	missense splice_region	Exon 56 of 63	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000298820.7	TSL:5	c.1525+87T>C		intron	N/A	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.34	T
PhyloP100		6.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-9.3	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0030	D
Vest4		0.85
MVP		0.59
MPC		0.18
ClinPred		1.0	D
GERP RS		5.4
gMVP		0.99
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs145929269; hg19: chr12-80752642;