8-101492563-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_024915.4(GRHL2):c.-207C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 669,400 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0052 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (2 hom.)
• Consequence: GRHL2 NM_024915.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.11

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 8-101492563-C-T is Benign according to our data. Variant chr8-101492563-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1187735.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00518 (789/152352) while in subpopulation AFR AF= 0.0176 (732/41580). AF 95% confidence interval is 0.0165. There are 9 homozygotes in gnomad4. There are 385 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRHL2	NM_024915.4	c.-207C>T		5_prime_UTR_variant	1/16	ENST00000646743.1
GRHL2	NM_001330593.2	c.-315C>T		5_prime_UTR_variant	1/16
GRHL2	XM_011517306.4	c.-52C>T		5_prime_UTR_variant	1/16
GRHL2	XM_011517307.4	c.-207C>T		5_prime_UTR_variant	1/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHL2	ENST00000646743.1	c.-207C>T		5_prime_UTR_variant	1/16		NM_024915.4	P1
GRHL2	ENST00000472106.2	n.122C>T		non_coding_transcript_exon_variant	1/2	1
GRHL2	ENST00000521085.1	c.-92C>T		5_prime_UTR_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.00516 AC: 785 AN: 152234 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00320

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000615 AC: 318 AN: 517048 Hom.: 2 Cov.: 4 AF XY: 0.000514 AC XY: 142 AN XY: 276008

Gnomad4 AFR exome AF: 0.0160

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000169

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.00518 AC: 789 AN: 152352 Hom.: 9 Cov.: 33 AF XY: 0.00517 AC XY: 385 AN XY: 74504

Gnomad4 AFR AF: 0.0176

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000615 Hom.: 0

Bravo AF: 0.00602

Asia WGS AF: 0.000289 AC: 1 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

Feb 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	18
Dann	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs141699759; hg19: chr8-102504791;