8-101543217-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024915.4(GRHL2):c.21-24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,599,380 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (31 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (30 hom.)
• Consequence: GRHL2 NM_024915.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.426

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 8-101543217-C-T is Benign according to our data. Variant chr8-101543217-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1188420.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0109 (1665/152206) while in subpopulation AFR AF= 0.0376 (1563/41520). AF 95% confidence interval is 0.0361. There are 31 homozygotes in gnomad4. There are 773 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 31 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRHL2	NM_024915.4	c.21-24C>T		intron_variant		ENST00000646743.1
GRHL2	NM_001330593.2	c.-28-24C>T		intron_variant
GRHL2	XM_011517306.4	c.-28-24C>T		intron_variant
GRHL2	XM_011517307.4	c.21-24C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHL2	ENST00000646743.1	c.21-24C>T		intron_variant			NM_024915.4	P1
GRHL2	ENST00000472106.2	n.349-24C>T		intron_variant, non_coding_transcript_variant		1
GRHL2	ENST00000395927.1	c.-28-24C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1653 AN: 152090 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00293 AC: 735 AN: 251238 Hom.: 13 AF XY: 0.00205 AC XY: 278 AN XY: 135798

Gnomad AFR exome AF: 0.0377

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00115 AC: 1667 AN: 1447174 Hom.: 30 Cov.: 28 AF XY: 0.00101 AC XY: 726 AN XY: 721032

Gnomad4 AFR exome AF: 0.0383

Gnomad4 AMR exome AF: 0.00269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000937

Gnomad4 OTH exome AF: 0.00252

GnomAD4 genome AF: 0.0109 AC: 1665 AN: 152206 Hom.: 31 Cov.: 32 AF XY: 0.0104 AC XY: 773 AN XY: 74426

Gnomad4 AFR AF: 0.0376

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00502 Hom.: 3

Bravo AF: 0.0127

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	10
Dann	Benign	0.68

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: rs73701923; hg19: chr8-102555445;