8-101492746-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_024915.4(GRHL2):c.-24C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,612,880 control chromosomes in the GnomAD database, including 791,254 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74236 hom., cov: 32)
  • Exomes 𝑓: 0.99 (717018 hom.)
• Consequence: GRHL2 NM_024915.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.18

Genes affected

GRHL2 (HGNC:2799): (grainyhead like transcription factor 2) The protein encoded by this gene is a transcription factor that can act as a homodimer or as a heterodimer with either GRHL1 or GRHL3. Defects in this gene are a cause of non-syndromic sensorineural deafness autosomal dominant type 28 (DFNA28).[provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 8-101492746-C-G is Benign according to our data. Variant chr8-101492746-C-G is described in ClinVar as [Benign]. Clinvar id is 508097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-101492746-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRHL2	NM_024915.4	c.-24C>G		5_prime_UTR_variant	1/16	ENST00000646743.1
GRHL2	NM_001330593.2	c.-132C>G		5_prime_UTR_variant	1/16
GRHL2	XM_011517307.4	c.-24C>G		5_prime_UTR_variant	1/16
GRHL2	XM_011517306.4	c.-29+160C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHL2	ENST00000646743.1	c.-24C>G		5_prime_UTR_variant	1/16		NM_024915.4	P1
GRHL2	ENST00000472106.2	n.305C>G		non_coding_transcript_exon_variant	1/2	1
GRHL2	ENST00000521085.1	c.-24C>G		5_prime_UTR_variant	2/2	3
GRHL2	ENST00000395927.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.987 AC: 150202 AN: 152204 Hom.: 74191 Cov.: 32

Gnomad AFR AF: 0.998

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.929

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.900

Gnomad SAS AF: 0.965

Gnomad FIN AF: 0.995

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.986

GnomAD3 exomes AF: 0.969 AC: 241444 AN: 249050 Hom.: 117346 AF XY: 0.973 AC XY: 131217 AN XY: 134826

Gnomad AFR exome AF: 0.998

Gnomad AMR exome AF: 0.871

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 0.901

Gnomad SAS exome AF: 0.968

Gnomad FIN exome AF: 0.995

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.984

GnomAD4 exome AF: 0.990 AC: 1446647 AN: 1460558 Hom.: 717018 Cov.: 37 AF XY: 0.990 AC XY: 719603 AN XY: 726692

Gnomad4 AFR exome AF: 0.998

Gnomad4 AMR exome AF: 0.878

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 0.903

Gnomad4 SAS exome AF: 0.967

Gnomad4 FIN exome AF: 0.995

Gnomad4 NFE exome AF: 0.999

Gnomad4 OTH exome AF: 0.988

GnomAD4 genome AF: 0.987 AC: 150305 AN: 152322 Hom.: 74236 Cov.: 32 AF XY: 0.985 AC XY: 73324 AN XY: 74478

Gnomad4 AFR AF: 0.998

Gnomad4 AMR AF: 0.929

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 0.900

Gnomad4 SAS AF: 0.966

Gnomad4 FIN AF: 0.995

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.982

Alfa AF: 0.995 Hom.: 13830

Bravo AF: 0.981

Asia WGS AF: 0.931 AC: 3238 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Corneal dystrophy, posterior polymorphous, 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 09, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Autosomal dominant nonsyndromic hearing loss 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	21
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs515622; hg19: chr8-102504974;