8-101659184-T-C

Variant names:

• chr8-101659184-T-C
• rs4734037
• NM_024915.4:c.1699-5270T>C

Variant summary

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

The NM_024915.4(GRHL2):​c.1699-5270T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 152,116 control chromosomes in the GnomAD database, including 4,714 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 0.24 (4714 hom., cov: 32)
• Consequence: GRHL2 NM_024915.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.883
• Publications: 6 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.1699-5270T>C		intron_variant	Intron 14 of 15	ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2	c.1651-5270T>C		intron_variant	Intron 14 of 15		NP_001317522.1
GRHL2	NM_001440448.1	c.1651-5270T>C		intron_variant	Intron 14 of 15		NP_001427377.1
GRHL2	NM_001440447.1	c.1699-5270T>C		intron_variant	Intron 14 of 15		NP_001427376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.1699-5270T>C		intron_variant	Intron 14 of 15		NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000395927.1	c.1651-5270T>C		intron_variant	Intron 14 of 15	2		ENSP00000379260.1
GRHL2	ENST00000474338.1	n.341-5270T>C		intron_variant	Intron 3 of 3	3
GRHL2	ENST00000517674.5	n.268-5270T>C		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37061 AN: 151998 Hom.: 4713 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.231

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

GnomAD4 genome AF: 0.244 AC: 37083 AN: 152116 Hom.: 4714 Cov.: 32 AF XY: 0.245 AC XY: 18201 AN XY: 74374

African (AFR) AF: 0.288 AC: 11928 AN: 41472

American (AMR) AF: 0.279 AC: 4255 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 802 AN: 3468

East Asian (EAS) AF: 0.249 AC: 1292 AN: 5182

South Asian (SAS) AF: 0.290 AC: 1396 AN: 4816

European-Finnish (FIN) AF: 0.202 AC: 2140 AN: 10594

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14629 AN: 67988

Other (OTH) AF: 0.228 AC: 481 AN: 2112

Alfa AF: 0.161 Hom.: 418

Bravo AF: 0.249

Asia WGS AF: 0.266 AC: 929 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.78
PhyloP100		-0.88
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: rs4734037; hg19: chr8-102671412;