8-101493333-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_024915.4(GRHL2):c.20+544G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRHL2 NM_024915.4 intron
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 2.04

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-101493333-G-T is Pathogenic according to our data. Variant chr8-101493333-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 489403.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-101493333-G-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRHL2	NM_024915.4	c.20+544G>T		intron_variant		ENST00000646743.1
GRHL2	NM_001330593.2	c.-29+484G>T		intron_variant
GRHL2	XM_011517306.4	c.-29+747G>T		intron_variant
GRHL2	XM_011517307.4	c.20+544G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHL2	ENST00000646743.1	c.20+544G>T		intron_variant			NM_024915.4	P1
GRHL2	ENST00000472106.2	n.348+544G>T		intron_variant, non_coding_transcript_variant		1
GRHL2	ENST00000395927.1	c.-29+484G>T		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Corneal dystrophy, posterior polymorphous, 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 12, 2022

- -

Corneal dystrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Hardcastle Lab, UCL Institute of Ophthalmology

Feb 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	15
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554579878; hg19: chr8-102505561;