rs142083150

Positions:

• chr8-101636940-A-G

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.1517+12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000919 in 1,612,324 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (8 hom.)
• Consequence: GRHL2 NM_024915.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.03

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=-0.88).
• BP6: Variant 8-101636940-A-G is Benign according to our data. Variant chr8-101636940-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 163649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0042 (640/152202) while in subpopulation AFR AF= 0.0144 (596/41532). AF 95% confidence interval is 0.0134. There are 5 homozygotes in gnomad4. There are 299 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.1517+12A>G		intron_variant		ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2	c.1469+12A>G		intron_variant			NP_001317522.1
GRHL2	XM_011517306.4	c.1469+12A>G		intron_variant			XP_011515608.1
GRHL2	XM_011517307.4	c.1517+12A>G		intron_variant			XP_011515609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.1517+12A>G		intron_variant			NM_024915.4	ENSP00000495564	P1
GRHL2	ENST00000395927.1	c.1469+12A>G		intron_variant		2		ENSP00000379260
GRHL2	ENST00000474338.1	n.159+12A>G		intron_variant, non_coding_transcript_variant		3
GRHL2	ENST00000517674.5	n.172+12A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00419 AC: 637 AN: 152084 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00121 AC: 305 AN: 251236 Hom.: 1 AF XY: 0.000877 AC XY: 119 AN XY: 135756

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000576 AC: 841 AN: 1460122 Hom.: 8 Cov.: 30 AF XY: 0.000483 AC XY: 351 AN XY: 726514

Gnomad4 AFR exome AF: 0.0157

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00420 AC: 640 AN: 152202 Hom.: 5 Cov.: 32 AF XY: 0.00402 AC XY: 299 AN XY: 74420

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00228 Hom.: 0

Bravo AF: 0.00505

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

1517+12A>G in Intron 12 of GRHL2: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence and has been identified in 1.4% (53/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.was hington.edu/EVS; dbSNP rs142083150). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.042
DANN	Benign	0.62

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: rs142083150; hg19: chr8-102649168;