8-101543246-A-T

Position:

• chr8-101543246-A-T

Variant summary

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

The NM_024915.4(GRHL2):​c.26A>T​(p.Lys9Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K9R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRHL2 NM_024915.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.43

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.26A>T	p.Lys9Ile	missense_variant	2/16	ENST00000646743.1	NP_079191.2
GRHL2	XM_011517307.4	c.26A>T	p.Lys9Ile	missense_variant	2/16		XP_011515609.1
GRHL2	NM_001330593.2	c.-23A>T		5_prime_UTR_variant	2/16		NP_001317522.1
GRHL2	XM_011517306.4	c.-23A>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.26A>T	p.Lys9Ile	missense_variant	2/16		NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000472106.2	n.354A>T		non_coding_transcript_exon_variant	2/2	1
GRHL2	ENST00000395927	c.-23A>T		5_prime_UTR_variant	2/16	2		ENSP00000379260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	.;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		0.74	P;P
Vest4		0.55
MutPred		0.35		Loss of ubiquitination at K9 (P = 6e-04);Loss of ubiquitination at K9 (P = 6e-04);
MVP		0.15
MPC		1.5
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.47
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

LitVar

Other links and lift over

dbSNP: rs3735709; hg19: chr8-102555474;