NM_024915.4:c.20+674C>G

Variant names:

• chr8-101493463-C-G
• rs114871790
• NM_024915.4:c.20+674C>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+674C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 143,386 control chromosomes in the GnomAD database, including 2,390 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (2390 hom., cov: 30)
• Consequence: GRHL2 NM_024915.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0560
• Publications: 0 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=-0.53).
• BP6: Variant 8-101493463-C-G is Benign according to our data. Variant chr8-101493463-C-G is described in ClinVar as Benign. ClinVar VariationId is 1291945.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.314 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+674C>G		intron	N/A	NP_079191.2	Q6ISB3-1
	GRHL2	NM_001330593.2		c.-29+614C>G		intron	N/A	NP_001317522.1	Q6ISB3-2
	GRHL2	NM_001440448.1		c.-29+877C>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+674C>G		intron	N/A	ENSP00000495564.1	Q6ISB3-1
	GRHL2	ENST00000472106.2	TSL:1	n.348+674C>G		intron	N/A
	GRHL2	ENST00000395927.1	TSL:2	c.-29+614C>G		intron	N/A	ENSP00000379260.1	Q6ISB3-2

Frequencies

GnomAD3 genomes AF: 0.144 AC: 20700 AN: 143268 Hom.: 2377 Cov.: 30

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.00484

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0835

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.0884

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0500

Gnomad OTH AF: 0.130

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

GnomAD4 genome AF: 0.145 AC: 20750 AN: 143386 Hom.: 2390 Cov.: 30 AF XY: 0.147 AC XY: 10217 AN XY: 69546

African (AFR) AF: 0.319 AC: 12711 AN: 39848

American (AMR) AF: 0.118 AC: 1689 AN: 14264

Ashkenazi Jewish (ASJ) AF: 0.0835 AC: 282 AN: 3376

East Asian (EAS) AF: 0.245 AC: 1165 AN: 4750

South Asian (SAS) AF: 0.133 AC: 575 AN: 4336

European-Finnish (FIN) AF: 0.0884 AC: 810 AN: 9164

Middle Eastern (MID) AF: 0.120 AC: 33 AN: 274

European-Non Finnish (NFE) AF: 0.0500 AC: 3229 AN: 64592

Other (OTH) AF: 0.129 AC: 252 AN: 1956

Alfa AF: 0.0971 Hom.: 173

Bravo AF: 0.148

Asia WGS AF: 0.180 AC: 621 AN: 3466

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	-0.53
CADD	Benign	15
DANN	Benign	0.89
PhyloP100		-0.056
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: rs114871790; hg19: chr8-102505691;