rs34213258

Positions:

• chr8-101644185-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024915.4(GRHL2):​c.1572A>G​(p.Pro524=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0083 in 1,614,074 control chromosomes in the GnomAD database, including 352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (171 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (181 hom.)
• Consequence: GRHL2 NM_024915.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.382

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 8-101644185-A-G is Benign according to our data. Variant chr8-101644185-A-G is described in ClinVar as [Benign]. Clinvar id is 178610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.382 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRHL2	NM_024915.4	c.1572A>G	p.Pro524=	synonymous_variant	13/16	ENST00000646743.1
GRHL2	NM_001330593.2	c.1524A>G	p.Pro508=	synonymous_variant	13/16
GRHL2	XM_011517306.4	c.1524A>G	p.Pro508=	synonymous_variant	13/16
GRHL2	XM_011517307.4	c.1572A>G	p.Pro524=	synonymous_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHL2	ENST00000646743.1	c.1572A>G	p.Pro524=	synonymous_variant	13/16		NM_024915.4	P1
GRHL2	ENST00000395927.1	c.1524A>G	p.Pro508=	synonymous_variant	13/16	2
GRHL2	ENST00000474338.1	n.214A>G		non_coding_transcript_exon_variant	2/4	3
GRHL2	ENST00000517674.5	n.227A>G		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.0277 AC: 4223 AN: 152194 Hom.: 170 Cov.: 32

Gnomad AFR AF: 0.0827

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.0588

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00263

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0127 AC: 3185 AN: 251318 Hom.: 78 AF XY: 0.0104 AC XY: 1414 AN XY: 135822

Gnomad AFR exome AF: 0.0817

Gnomad AMR exome AF: 0.00703

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.0598

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.00291

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.00626 AC: 9152 AN: 1461762 Hom.: 181 Cov.: 31 AF XY: 0.00590 AC XY: 4289 AN XY: 727200

Gnomad4 AFR exome AF: 0.0841

Gnomad4 AMR exome AF: 0.00751

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.0509

Gnomad4 SAS exome AF: 0.00235

Gnomad4 FIN exome AF: 0.00294

Gnomad4 NFE exome AF: 0.00257

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.0279 AC: 4244 AN: 152312 Hom.: 171 Cov.: 32 AF XY: 0.0272 AC XY: 2023 AN XY: 74492

Gnomad4 AFR AF: 0.0830

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.0589

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00263

Gnomad4 NFE AF: 0.00293

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0149 Hom.: 40

Bravo AF: 0.0321

Asia WGS AF: 0.0220 AC: 77 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00207

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Pro524Pro in Exon 13 of GRHL2: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 7.8% (292/3738) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs34213258). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	4.3
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs34213258; hg19: chr8-102656413; COSMIC: COSV52544684;