rs55682875

chr8-101573737-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_024915.4(GRHL2):c.804C>T(p.Thr268=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000838 in 1,614,170 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 0.00075 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (0 hom.)
• Consequence: GRHL2 NM_024915.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.22

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 8-101573737-C-T is Benign according to our data. Variant chr8-101573737-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227417.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}. Variant chr8-101573737-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000749 (114/152298) while in subpopulation NFE AF= 0.00101 (69/68026). AF 95% confidence interval is 0.000821. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRHL2	NM_024915.4	c.804C>T	p.Thr268=	synonymous_variant	6/16	ENST00000646743.1
GRHL2	NM_001330593.2	c.756C>T	p.Thr252=	synonymous_variant	6/16
GRHL2	XM_011517306.4	c.756C>T	p.Thr252=	synonymous_variant	6/16
GRHL2	XM_011517307.4	c.804C>T	p.Thr268=	synonymous_variant	6/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHL2	ENST00000646743.1	c.804C>T	p.Thr268=	synonymous_variant	6/16		NM_024915.4	P1
GRHL2	ENST00000395927.1	c.756C>T	p.Thr252=	synonymous_variant	6/16	2

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000740 AC: 186 AN: 251478 Hom.: 0 AF XY: 0.000625 AC XY: 85 AN XY: 135918

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.000914

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000848 AC: 1239 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.000791 AC XY: 575 AN XY: 727240

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00109

Gnomad4 NFE exome AF: 0.000956

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.000645 AC XY: 48 AN XY: 74472

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.000752

EpiCase AF: 0.000763

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	GRHL2: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 24, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 27, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 28, 2016

Thr268Thr in Exon 06 of GRHL2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 58/66678 European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs55682875). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	12
Dann	Benign	0.63

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: rs55682875; hg19: chr8-102585965;