8-101492313-C-G

Variant names:

• chr8-101492313-C-G
• rs541154
• ENST00000520268.1:n.50+137G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NR_186783.1(GRHL2-DT):​n.257-8G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GRHL2-DT NR_186783.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.184
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).

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_186782.1		n.256+137G>C		intron	N/A
	GRHL2-DT	NR_186783.1		n.257-8G>C		splice_region intron	N/A
	GRHL2-DT	NR_186784.1		n.59-3G>C		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2-DT	ENST00000520268.1	TSL:3	n.50+137G>C		intron	N/A
	GRHL2-DT	ENST00000690034.2		n.67-8G>C		splice_region intron	N/A
	GRHL2-DT	ENST00000701971.2		n.425-3G>C		splice_region intron	N/A

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 36440 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 18878

African (AFR) AF: 0.00 AC: 0 AN: 1346

American (AMR) AF: 0.00 AC: 0 AN: 3370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 884

East Asian (EAS) AF: 0.00 AC: 0 AN: 2872

South Asian (SAS) AF: 0.00 AC: 0 AN: 3770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 122

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 20876

Other (OTH) AF: 0.00 AC: 0 AN: 1722

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 11073

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.9
DANN	Benign	0.82
PhyloP100		-0.18
PromoterAI		-0.015	Neutral

Splicing

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

Other links and lift over

dbSNP: rs541154; hg19: chr8-102504541;