chr8-101543303-C-A

Variant names:

• chr8-101543303-C-A
• NM_024915.4:c.83C>A

Variant summary

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

The NM_024915.4(GRHL2):​c.83C>A​(p.Ala28Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GRHL2 NM_024915.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91

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 rank	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.83C>A	p.Ala28Asp	missense_variant	Exon 2 of 16	ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2	c.35C>A	p.Ala12Asp	missense_variant	Exon 2 of 16		NP_001317522.1
GRHL2	XM_011517306.4	c.35C>A	p.Ala12Asp	missense_variant	Exon 2 of 16		XP_011515608.1
GRHL2	XM_011517307.4	c.83C>A	p.Ala28Asp	missense_variant	Exon 2 of 16		XP_011515609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.83C>A	p.Ala28Asp	missense_variant	Exon 2 of 16		NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000472106.2	n.411C>A		non_coding_transcript_exon_variant	Exon 2 of 2	1
GRHL2	ENST00000395927.1	c.35C>A	p.Ala12Asp	missense_variant	Exon 2 of 16	2		ENSP00000379260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;.
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.9	N;.;N
REVEL	Benign	0.22
Sift	Benign	0.058	T;.;T
Sift4G	Benign	0.22	T;.;T
Polyphen		0.57	P;P;.
Vest4		0.80
MutPred		0.15		Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);.;
MVP		0.043
MPC		0.97
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.24
gMVP		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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-102555531;