8-101540549-C-T

Variant names:

• chr8-101540549-C-T
• rs1981361
• NM_024915.4:c.21-2692C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024915.4(GRHL2):​c.21-2692C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 152,070 control chromosomes in the GnomAD database, including 19,645 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.49 (19645 hom., cov: 32)
• Consequence: GRHL2 NM_024915.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.21-2692C>T		intron_variant	Intron 1 of 15	ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2	c.-28-2692C>T		intron_variant	Intron 1 of 15		NP_001317522.1
GRHL2	NM_001440448.1	c.-28-2692C>T		intron_variant	Intron 1 of 15		NP_001427377.1
GRHL2	NM_001440447.1	c.21-2692C>T		intron_variant	Intron 1 of 15		NP_001427376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.21-2692C>T		intron_variant	Intron 1 of 15		NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000472106.2	n.349-2692C>T		intron_variant	Intron 1 of 1	1
GRHL2	ENST00000395927.1	c.-28-2692C>T		intron_variant	Intron 1 of 15	2		ENSP00000379260.1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75052 AN: 151952 Hom.: 19637 Cov.: 32

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.625

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.568

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.581

Gnomad OTH AF: 0.506

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.494 AC: 75098 AN: 152070 Hom.: 19645 Cov.: 32 AF XY: 0.492 AC XY: 36547 AN XY: 74324

African (AFR) AF: 0.361 AC: 14958 AN: 41468

American (AMR) AF: 0.491 AC: 7506 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.568 AC: 1971 AN: 3470

East Asian (EAS) AF: 0.276 AC: 1426 AN: 5170

South Asian (SAS) AF: 0.285 AC: 1376 AN: 4822

European-Finnish (FIN) AF: 0.626 AC: 6616 AN: 10574

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.581 AC: 39481 AN: 67972

Other (OTH) AF: 0.503 AC: 1063 AN: 2112

Alfa AF: 0.543 Hom.: 27360

Bravo AF: 0.481

Asia WGS AF: 0.298 AC: 1037 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.30
DANN	Benign	0.66
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs1981361; hg19: chr8-102552777;