8-101666577-C-G

Position:

• chr8-101666577-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_024915.4(GRHL2):​c.1764-12C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000758 in 1,529,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: GRHL2 NM_024915.4 intron
• Scores: Splicing: ADA: 0.0001986
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -3.02

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-101666577-C-G is Benign according to our data. Variant chr8-101666577-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228732.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000719 (99/1377384) while in subpopulation MID AF= 0.00124 (7/5634). AF 95% confidence interval is 0.000582. There are 0 homozygotes in gnomad4_exome. There are 51 alleles in male gnomad4_exome subpopulation. Median coverage is 24. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.1764-12C>G		intron_variant		ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2	c.1716-12C>G		intron_variant			NP_001317522.1
GRHL2	XM_011517306.4	c.1716-12C>G		intron_variant			XP_011515608.1
GRHL2	XM_011517307.4	c.1763+2059C>G		intron_variant			XP_011515609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.1764-12C>G		intron_variant			NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000395927.1	c.1716-12C>G		intron_variant		2		ENSP00000379260.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000104 AC: 26 AN: 251028 Hom.: 0 AF XY: 0.0000958 AC XY: 13 AN XY: 135654

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000719 AC: 99 AN: 1377384 Hom.: 0 Cov.: 24 AF XY: 0.0000739 AC XY: 51 AN XY: 690308

Gnomad4 AFR exome AF: 0.000347

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.000117

Gnomad4 EAS exome AF: 0.000153

Gnomad4 SAS exome AF: 0.000177

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000348

Gnomad4 OTH exome AF: 0.000209

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74436

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000170

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 18, 2016

The c.1764-12C>G variant in GRHL2 has been reported by our laboratory in one ind ividual with hearing loss. This variant was identified in 5/16156 South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs371424751); however, its frequency is not high enough to rule out a pathogenic role. This variant is located in the 3' splice region. Computational tools do not suggest an impact to splicing; however, this information is not pr edictive enough to rule out pathogenicity. In summary, the clinical significance of the c.1764-12C>G variant is uncertain. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.012
DANN	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.020		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: rs371424751; hg19: chr8-102678805;