8-101570349-G-C

Variant names:

• chr8-101570349-G-C
• rs140423160
• NM_024915.4:c.689G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024915.4(GRHL2):​c.689G>C​(p.Ser230Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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: 4.66

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14899576).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.689G>C	p.Ser230Thr	missense_variant	Exon 5 of 16	ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2	c.641G>C	p.Ser214Thr	missense_variant	Exon 5 of 16		NP_001317522.1
GRHL2	XM_011517306.4	c.641G>C	p.Ser214Thr	missense_variant	Exon 5 of 16		XP_011515608.1
GRHL2	XM_011517307.4	c.689G>C	p.Ser230Thr	missense_variant	Exon 5 of 16		XP_011515609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.689G>C	p.Ser230Thr	missense_variant	Exon 5 of 16		NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000395927.1	c.641G>C	p.Ser214Thr	missense_variant	Exon 5 of 16	2		ENSP00000379260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251392 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461638 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.070	T;T;.
Eigen	Benign	-0.069
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	.;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N;N;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.85	N;.;N
REVEL	Benign	0.031
Sift	Benign	1.0	T;.;T
Sift4G	Benign	0.42	T;.;T
Polyphen		0.0010	B;B;.
Vest4		0.38
MutPred		0.47		Gain of methylation at K227 (P = 0.0981);Gain of methylation at K227 (P = 0.0981);.;
MVP		0.068
MPC		0.33
ClinPred		0.13	T
GERP RS		5.3
Varity_R		0.12
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140423160; hg19: chr8-102582577;