8-101558682-G-T

Variant names:

• chr8-101558682-G-T
• rs142411476
• NM_024915.4:c.548G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024915.4(GRHL2):​c.548G>T​(p.Arg183Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. R183Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GRHL2 NM_024915.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.22
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 28

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• posterior polymorphous corneal dystrophy

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P
• nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital fibrosis of extraocular muscles

  Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26646566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.548G>T	p.Arg183Leu	missense_variant	Exon 4 of 16	ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2	c.500G>T	p.Arg167Leu	missense_variant	Exon 4 of 16		NP_001317522.1
GRHL2	NM_001440448.1	c.500G>T	p.Arg167Leu	missense_variant	Exon 4 of 16		NP_001427377.1
GRHL2	NM_001440447.1	c.548G>T	p.Arg183Leu	missense_variant	Exon 4 of 16		NP_001427376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.548G>T	p.Arg183Leu	missense_variant	Exon 4 of 16		NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000395927.1	c.500G>T	p.Arg167Leu	missense_variant	Exon 4 of 16	2		ENSP00000379260.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.
PhyloP100		5.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.2	N;.;N
REVEL	Benign	0.096
Sift	Benign	0.14	T;.;T
Sift4G	Benign	0.41	T;.;T
Polyphen		0.0040	B;B;.
Vest4		0.72
MutPred		0.48		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;
MVP		0.068
MPC		0.44
ClinPred		0.84	D
GERP RS		5.3
Varity_R		0.13
gMVP		0.68
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs142411476; hg19: chr8-102570910;