8-101492746-C-G

Variant names:

• chr8-101492746-C-G
• rs515622
• NM_024915.4:c.-24C>G

Variant summary

Our verdict is Benign. The variant received -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:6
• Conservation: PhyloP100: 3.18
• Publications: 12 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-DT (HGNC:):

GRHL2-DT (HGNC:55466): (GRHL2 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 508097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 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.-24C>G		5_prime_UTR	Exon 1 of 16	NP_079191.2	Q6ISB3-1
	GRHL2	NM_001330593.2		c.-132C>G		5_prime_UTR	Exon 1 of 16	NP_001317522.1	Q6ISB3-2
	GRHL2	NM_001440447.1		c.-24C>G		5_prime_UTR	Exon 1 of 16	NP_001427376.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2	ENST00000646743.1	MANE Select	c.-24C>G		5_prime_UTR	Exon 1 of 16	ENSP00000495564.1	Q6ISB3-1
	GRHL2	ENST00000472106.2	TSL:1	n.305C>G		non_coding_transcript_exon	Exon 1 of 2
	GRHL2	ENST00000907653.1		c.-24C>G		5_prime_UTR	Exon 1 of 14	ENSP00000577712.1

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

GnomAD2 exomes AF: 0.969 AC: 241444 AN: 249050 AF XY: 0.973

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 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

African (AFR) AF: 0.998 AC: 33378 AN: 33446

American (AMR) AF: 0.878 AC: 39249 AN: 44712

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26129 AN: 26130

East Asian (EAS) AF: 0.903 AC: 35826 AN: 39690

South Asian (SAS) AF: 0.967 AC: 83357 AN: 86218

European-Finnish (FIN) AF: 0.995 AC: 53141 AN: 53410

Middle Eastern (MID) AF: 0.994 AC: 5728 AN: 5762

European-Non Finnish (NFE) AF: 0.999 AC: 1110236 AN: 1110848

Other (OTH) AF: 0.988 AC: 59603 AN: 60342

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

African (AFR) AF: 0.998 AC: 41497 AN: 41590

American (AMR) AF: 0.929 AC: 14215 AN: 15304

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 0.900 AC: 4650 AN: 5166

South Asian (SAS) AF: 0.966 AC: 4658 AN: 4824

European-Finnish (FIN) AF: 0.995 AC: 10565 AN: 10620

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67975 AN: 68034

Other (OTH) AF: 0.982 AC: 2068 AN: 2106

Alfa AF: 0.995 Hom.: 13830

Bravo AF: 0.981

Asia WGS AF: 0.931 AC: 3238 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Corneal dystrophy, posterior polymorphous, 4 (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 28 (1)
-	-	1	Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.92
PhyloP100		3.2
PromoterAI		-0.11	Neutral
Mutation Taster		=297/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs515622; hg19: chr8-102504974;