8-101492283-G-A

Variant names:

• chr8-101492283-G-A
• rs541226
• ENST00000690034.2:n.89C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NR_186783.1(GRHL2-DT):​n.279C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.975 in 171,398 control chromosomes in the GnomAD database, including 81,567 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.98 (72606 hom., cov: 34)
  • Exomes 𝑓: 0.97 (8961 hom.)
• Consequence: GRHL2-DT NR_186783.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0780
• Publications: 1 publications found

Genes affected

GRHL2-DT (HGNC:):

GRHL2-DT (HGNC:55466): (GRHL2 divergent transcript)

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):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss 28

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 8-101492283-G-A is Benign according to our data. Variant chr8-101492283-G-A is described in ClinVar as Benign. ClinVar VariationId is 1278689.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NR_186783.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2-DT	NR_186783.1		n.279C>T		non_coding_transcript_exon	Exon 2 of 2
	GRHL2-DT	NR_186784.1		n.86C>T		non_coding_transcript_exon	Exon 2 of 3
	GRHL2-DT	NR_186782.1		n.256+167C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2-DT	ENST00000690034.2		n.89C>T		non_coding_transcript_exon	Exon 2 of 3
	GRHL2-DT	ENST00000701971.2		n.452C>T		non_coding_transcript_exon	Exon 2 of 2
	GRHL2-DT	ENST00000716505.1		n.93C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.976 AC: 148553 AN: 152238 Hom.: 72569 Cov.: 34

Gnomad AFR AF: 0.960

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.922

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 0.902

Gnomad SAS AF: 0.965

Gnomad FIN AF: 0.995

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.982

GnomAD4 exome AF: 0.969 AC: 18456 AN: 19042 Hom.: 8961 AF XY: 0.968 AC XY: 9651 AN XY: 9972

African (AFR) AF: 0.959 AC: 516 AN: 538

American (AMR) AF: 0.896 AC: 2381 AN: 2658

Ashkenazi Jewish (ASJ) AF: 0.997 AC: 339 AN: 340

East Asian (EAS) AF: 0.890 AC: 1329 AN: 1494

South Asian (SAS) AF: 0.957 AC: 1850 AN: 1934

European-Finnish (FIN) AF: 0.990 AC: 871 AN: 880

Middle Eastern (MID) AF: 1.00 AC: 40 AN: 40

European-Non Finnish (NFE) AF: 0.998 AC: 10322 AN: 10342

Other (OTH) AF: 0.990 AC: 808 AN: 816

GnomAD4 genome AF: 0.976 AC: 148647 AN: 152356 Hom.: 72606 Cov.: 34 AF XY: 0.974 AC XY: 72575 AN XY: 74494

African (AFR) AF: 0.960 AC: 39917 AN: 41592

American (AMR) AF: 0.922 AC: 14108 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 3469 AN: 3472

East Asian (EAS) AF: 0.902 AC: 4662 AN: 5170

South Asian (SAS) AF: 0.965 AC: 4661 AN: 4828

European-Finnish (FIN) AF: 0.995 AC: 10573 AN: 10628

Middle Eastern (MID) AF: 0.990 AC: 291 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67982 AN: 68042

Other (OTH) AF: 0.979 AC: 2072 AN: 2116

Alfa AF: 0.977 Hom.: 12460

Bravo AF: 0.968

Asia WGS AF: 0.927 AC: 3225 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.94
PhyloP100		0.078
PromoterAI		0.021	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs541226; hg19: chr8-102504511;