8-101666570-C-T

Position:

• chr8-101666570-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024915.4(GRHL2):​c.1764-19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,471,252 control chromosomes in the GnomAD database, including 102,143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11132 hom., cov: 31)
  • Exomes 𝑓: 0.37 (91011 hom.)
• Consequence: GRHL2 NM_024915.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.67

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=-0.84).
• BP6: Variant 8-101666570-C-T is Benign according to our data. Variant chr8-101666570-C-T is described in ClinVar as [Benign]. Clinvar id is 261793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-101666570-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.1764-19C>T		intron_variant		ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2	c.1716-19C>T		intron_variant			NP_001317522.1
GRHL2	XM_011517306.4	c.1716-19C>T		intron_variant			XP_011515608.1
GRHL2	XM_011517307.4	c.1763+2052C>T		intron_variant			XP_011515609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.1764-19C>T		intron_variant			NM_024915.4	ENSP00000495564	P1
GRHL2	ENST00000395927.1	c.1716-19C>T		intron_variant		2		ENSP00000379260

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57324 AN: 151710 Hom.: 11114 Cov.: 31

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.376

GnomAD3 exomes AF: 0.390 AC: 97367 AN: 249724 Hom.: 19701 AF XY: 0.392 AC XY: 52855 AN XY: 134854

Gnomad AFR exome AF: 0.424

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.373

Gnomad EAS exome AF: 0.348

Gnomad SAS exome AF: 0.538

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.345

Gnomad OTH exome AF: 0.387

GnomAD4 exome AF: 0.366 AC: 482787 AN: 1319424 Hom.: 91011 Cov.: 20 AF XY: 0.370 AC XY: 245865 AN XY: 664060

Gnomad4 AFR exome AF: 0.431

Gnomad4 AMR exome AF: 0.457

Gnomad4 ASJ exome AF: 0.369

Gnomad4 EAS exome AF: 0.357

Gnomad4 SAS exome AF: 0.534

Gnomad4 FIN exome AF: 0.322

Gnomad4 NFE exome AF: 0.348

Gnomad4 OTH exome AF: 0.374

GnomAD4 genome AF: 0.378 AC: 57386 AN: 151828 Hom.: 11132 Cov.: 31 AF XY: 0.380 AC XY: 28215 AN XY: 74160

Gnomad4 AFR AF: 0.424

Gnomad4 AMR AF: 0.415

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.348

Gnomad4 SAS AF: 0.539

Gnomad4 FIN AF: 0.315

Gnomad4 NFE AF: 0.344

Gnomad4 OTH AF: 0.377

Alfa AF: 0.358 Hom.: 1908

Bravo AF: 0.382

Asia WGS AF: 0.514 AC: 1790 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Corneal dystrophy, posterior polymorphous, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Autosomal dominant nonsyndromic hearing loss 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.18
DANN	Benign	0.55

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: rs10093032; hg19: chr8-102678798; COSMIC: COSV52548876; COSMIC: COSV52548876;