rs749906501

Positions:

• chr8-101543254-G-A
• chr8-101543254-G-T

Variant summary

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

The NM_001330593.2(GRHL2):​c.-15G>A variant causes a 5 prime UTR premature start codon gain 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRHL2 NM_001330593.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.29

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]

GRHL2 (HGNC:):

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.34G>A	p.Val12Met	missense_variant	2/16	ENST00000646743.1	NP_079191.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.34G>A	p.Val12Met	missense_variant	2/16		NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000472106.2	n.362G>A		non_coding_transcript_exon_variant	2/2	1
GRHL2	ENST00000395927.1	c.-15G>A		5_prime_UTR_premature_start_codon_gain_variant	2/16	2		ENSP00000379260.1
GRHL2	ENST00000395927.1	c.-15G>A		5_prime_UTR_variant	2/16	2		ENSP00000379260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.99	N;.
REVEL	Benign	0.28
Sift	Uncertain	0.0090	D;.
Sift4G	Uncertain	0.045	D;.
Polyphen		1.0	D;D
Vest4		0.64
MutPred		0.31		Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);
MVP		0.24
MPC		1.1
ClinPred		0.92	D
GERP RS		6.0
Varity_R		0.21
gMVP		0.66

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: rs749906501; hg19: chr8-102555482;