8-101543266-C-T

Position:

• chr8-101543266-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024915.4(GRHL2):​c.46C>T​(p.Pro16Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,638 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GRHL2 NM_024915.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.46C>T	p.Pro16Ser	missense_variant	2/16	ENST00000646743.1	NP_079191.2
GRHL2	XM_011517307.4	c.46C>T	p.Pro16Ser	missense_variant	2/16		XP_011515609.1
GRHL2	NM_001330593.2	c.-3C>T		5_prime_UTR_variant	2/16		NP_001317522.1
GRHL2	XM_011517306.4	c.-3C>T		5_prime_UTR_variant	2/16		XP_011515608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.46C>T	p.Pro16Ser	missense_variant	2/16		NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000472106.2	n.374C>T		non_coding_transcript_exon_variant	2/2	1
GRHL2	ENST00000395927	c.-3C>T		5_prime_UTR_variant	2/16	2		ENSP00000379260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461638 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727144

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2024

The c.46C>T (p.P16S) alteration is located in exon 2 (coding exon 2) of the GRHL2 gene. This alteration results from a C to T substitution at nucleotide position 46, causing the proline (P) at amino acid position 16 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	.;T
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.11
Sift	Benign	0.032	D;.
Sift4G	Benign	0.14	T;.
Polyphen		0.99	D;D
Vest4		0.50
MutPred		0.27		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.043
MPC		1.1
ClinPred		0.88	D
GERP RS		5.1
Varity_R		0.10
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-102555494;