8-101666631-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024915.4(GRHL2):c.1806G>C(p.Ser602=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,613,476 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S602S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0056 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (8 hom.)
• Consequence: GRHL2 NM_024915.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.20

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=-0.57).
• BP6: Variant 8-101666631-G-C is Benign according to our data. Variant chr8-101666631-G-C is described in ClinVar as [Benign]. Clinvar id is 46217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00555 (845/152142) while in subpopulation AFR AF= 0.0192 (796/41504). AF 95% confidence interval is 0.0181. There are 10 homozygotes in gnomad4. There are 400 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRHL2	NM_024915.4	c.1806G>C	p.Ser602=	synonymous_variant	16/16	ENST00000646743.1
GRHL2	NM_001330593.2	c.1758G>C	p.Ser586=	synonymous_variant	16/16
GRHL2	XM_011517306.4	c.1758G>C	p.Ser586=	synonymous_variant	16/16
GRHL2	XM_011517307.4	c.1763+2113G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHL2	ENST00000646743.1	c.1806G>C	p.Ser602=	synonymous_variant	16/16		NM_024915.4	P1
GRHL2	ENST00000395927.1	c.1758G>C	p.Ser586=	synonymous_variant	16/16	2

Frequencies

GnomAD3 genomes AF: 0.00550 AC: 836 AN: 152024 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00178 AC: 448 AN: 251384 Hom.: 3 AF XY: 0.00150 AC XY: 204 AN XY: 135852

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.000715 AC: 1045 AN: 1461334 Hom.: 8 Cov.: 31 AF XY: 0.000693 AC XY: 504 AN XY: 727022

Gnomad4 AFR exome AF: 0.0199

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000603

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00555 AC: 845 AN: 152142 Hom.: 10 Cov.: 32 AF XY: 0.00538 AC XY: 400 AN XY: 74364

Gnomad4 AFR AF: 0.0192

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000775

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.000424 Hom.: 0

Bravo AF: 0.00607

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Ser602Ser in Exon 16 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 1.7% (64/3738) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs61732855). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	0.12
Dann	Benign	0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs61732855; hg19: chr8-102678859;