NM_024915.4:c.20+688A>G

Variant names:

• chr8-101493477-A-G
• rs581752
• NM_024915.4:c.20+688A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024915.4(GRHL2):​c.20+688A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.811 in 150,206 control chromosomes in the GnomAD database, including 50,673 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.81 (50673 hom., cov: 30)
• Consequence: GRHL2 NM_024915.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.814
• Publications: 2 publications found

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]

GRHL2 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss 28

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• posterior polymorphous corneal dystrophy

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P
• nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital fibrosis of extraocular muscles

  Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp

GRHL2-DT (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 8-101493477-A-G is Benign according to our data. Variant chr8-101493477-A-G is described in ClinVar as Benign. ClinVar VariationId is 1243960.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024915.4. 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
	GRHL2	NM_024915.4	MANE Select	c.20+688A>G		intron	N/A	NP_079191.2	Q6ISB3-1
	GRHL2	NM_001330593.2		c.-29+628A>G		intron	N/A	NP_001317522.1	Q6ISB3-2
	GRHL2	NM_001440448.1		c.-29+891A>G		intron	N/A	NP_001427377.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2	ENST00000646743.1	MANE Select	c.20+688A>G		intron	N/A	ENSP00000495564.1	Q6ISB3-1
	GRHL2	ENST00000472106.2	TSL:1	n.348+688A>G		intron	N/A
	GRHL2	ENST00000395927.1	TSL:2	c.-29+628A>G		intron	N/A	ENSP00000379260.1	Q6ISB3-2

Frequencies

GnomAD3 genomes AF: 0.812 AC: 121848 AN: 150126 Hom.: 50672 Cov.: 30

Gnomad AFR AF: 0.597

Gnomad AMI AF: 0.983

Gnomad AMR AF: 0.805

Gnomad ASJ AF: 0.881

Gnomad EAS AF: 0.697

Gnomad SAS AF: 0.816

Gnomad FIN AF: 0.912

Gnomad MID AF: 0.844

Gnomad NFE AF: 0.926

Gnomad OTH AF: 0.834

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

GnomAD4 genome AF: 0.811 AC: 121880 AN: 150206 Hom.: 50673 Cov.: 30 AF XY: 0.810 AC XY: 59488 AN XY: 73406

African (AFR) AF: 0.596 AC: 24059 AN: 40354

American (AMR) AF: 0.805 AC: 12190 AN: 15142

Ashkenazi Jewish (ASJ) AF: 0.881 AC: 3055 AN: 3466

East Asian (EAS) AF: 0.697 AC: 3387 AN: 4858

South Asian (SAS) AF: 0.816 AC: 3889 AN: 4764

European-Finnish (FIN) AF: 0.912 AC: 9599 AN: 10526

Middle Eastern (MID) AF: 0.853 AC: 249 AN: 292

European-Non Finnish (NFE) AF: 0.926 AC: 62815 AN: 67804

Other (OTH) AF: 0.834 AC: 1744 AN: 2092

Alfa AF: 0.860 Hom.: 6615

Bravo AF: 0.784

Asia WGS AF: 0.732 AC: 2527 AN: 3454

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	10
DANN	Benign	0.83
PhyloP100		-0.81
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs581752; hg19: chr8-102505705;