rs666026

Variant names:

• chr8-101544990-C-A
• rs666026
• NM_024915.4:c.216+1554C>A

Your query was ambiguous. Multiple possible variants found:

• chr8-101544990-C-A
• chr8-101544990-C-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024915.4(GRHL2):​c.216+1554C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.903 in 152,106 control chromosomes in the GnomAD database, including 62,215 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.90 (62215 hom., cov: 31)
• Consequence: GRHL2 NM_024915.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.519
• Publications: 8 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):

• autosomal dominant nonsyndromic hearing loss 28

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.931 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2	NM_024915.4	MANE Select	c.216+1554C>A		intron	N/A	NP_079191.2
	GRHL2	NM_001330593.2		c.168+1554C>A		intron	N/A	NP_001317522.1
	GRHL2	NM_001440448.1		c.168+1554C>A		intron	N/A	NP_001427377.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2	ENST00000646743.1	MANE Select	c.216+1554C>A		intron	N/A	ENSP00000495564.1
	GRHL2	ENST00000395927.1	TSL:2	c.168+1554C>A		intron	N/A	ENSP00000379260.1

Frequencies

GnomAD3 genomes AF: 0.903 AC: 137228 AN: 151990 Hom.: 62161 Cov.: 31

Gnomad AFR AF: 0.882

Gnomad AMI AF: 0.976

Gnomad AMR AF: 0.885

Gnomad ASJ AF: 0.909

Gnomad EAS AF: 0.683

Gnomad SAS AF: 0.904

Gnomad FIN AF: 0.893

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.937

Gnomad OTH AF: 0.900

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

GnomAD4 genome AF: 0.903 AC: 137335 AN: 152106 Hom.: 62215 Cov.: 31 AF XY: 0.901 AC XY: 66995 AN XY: 74326

African (AFR) AF: 0.882 AC: 36599 AN: 41482

American (AMR) AF: 0.884 AC: 13509 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.909 AC: 3155 AN: 3472

East Asian (EAS) AF: 0.683 AC: 3526 AN: 5164

South Asian (SAS) AF: 0.903 AC: 4336 AN: 4802

European-Finnish (FIN) AF: 0.893 AC: 9451 AN: 10586

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.937 AC: 63733 AN: 68008

Other (OTH) AF: 0.900 AC: 1895 AN: 2106

Alfa AF: 0.926 Hom.: 108826

Bravo AF: 0.900

Asia WGS AF: 0.803 AC: 2794 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.21
DANN	Benign	0.60
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

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: rs666026; hg19: chr8-102557218;