rs189993760

Positions:

• chr8-101599160-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024915.4(GRHL2):​c.1098+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00522 in 1,549,974 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0054 (25 hom.)
• Consequence: GRHL2 NM_024915.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.535

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-101599160-C-T is Benign according to our data. Variant chr8-101599160-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-101599160-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00365 (556/152272) while in subpopulation NFE AF= 0.00648 (441/68020). AF 95% confidence interval is 0.00598. There are 1 homozygotes in gnomad4. There are 243 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 25 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRHL2	NM_024915.4	c.1098+9C>T		intron_variant		ENST00000646743.1
GRHL2	NM_001330593.2	c.1050+9C>T		intron_variant
GRHL2	XM_011517306.4	c.1050+9C>T		intron_variant
GRHL2	XM_011517307.4	c.1098+9C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHL2	ENST00000646743.1	c.1098+9C>T		intron_variant			NM_024915.4	P1
GRHL2	ENST00000395927.1	c.1050+9C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 556 AN: 152154 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00648

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00331 AC: 831 AN: 250756 Hom.: 5 AF XY: 0.00341 AC XY: 462 AN XY: 135522

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000754

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00605

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00539 AC: 7537 AN: 1397702 Hom.: 25 Cov.: 23 AF XY: 0.00516 AC XY: 3607 AN XY: 699144

Gnomad4 AFR exome AF: 0.000994

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.000311

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000612

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.00672

Gnomad4 OTH exome AF: 0.00371

GnomAD4 genome AF: 0.00365 AC: 556 AN: 152272 Hom.: 1 Cov.: 31 AF XY: 0.00326 AC XY: 243 AN XY: 74452

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.00648

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00447 Hom.: 2

Bravo AF: 0.00351

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	1098+9C>T in Intron 08 of GRHL2: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence and has been identified in 0.6% (45/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.was hington.edu/EVS). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	GRHL2: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Autosomal dominant nonsyndromic hearing loss 28;C4014987:Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome;C4747961:Corneal dystrophy, posterior polymorphous, 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.29

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: rs189993760; hg19: chr8-102611388;