chr8-101492313-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NR_186783.1(GRHL2-DT):​n.257-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.967 in 188,778 control chromosomes in the GnomAD database, including 88,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71128 hom., cov: 34)
  • Exomes 𝑓: 0.97 (17285 hom.)
• Consequence: GRHL2-DT NR_186783.1 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 8-101492313-C-T is Benign according to our data. Variant chr8-101492313-C-T is described in ClinVar as Benign. ClinVar VariationId is 1222504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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_186782.1		n.256+137G>A		intron	N/A
	GRHL2-DT	NR_186783.1		n.257-8G>A		splice_region intron	N/A
	GRHL2-DT	NR_186784.1		n.59-3G>A		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>A		intron	N/A
	GRHL2-DT	ENST00000690034.2		n.67-8G>A		splice_region intron	N/A
	GRHL2-DT	ENST00000701971.2		n.425-3G>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.966 AC: 146999 AN: 152230 Hom.: 71100 Cov.: 34

Gnomad AFR AF: 0.924

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.919

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 0.903

Gnomad SAS AF: 0.965

Gnomad FIN AF: 0.995

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.974

GnomAD4 exome AF: 0.973 AC: 35459 AN: 36430 Hom.: 17285 AF XY: 0.973 AC XY: 18357 AN XY: 18874

African (AFR) AF: 0.924 AC: 1242 AN: 1344

American (AMR) AF: 0.894 AC: 3009 AN: 3366

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 883 AN: 884

East Asian (EAS) AF: 0.898 AC: 2577 AN: 2870

South Asian (SAS) AF: 0.960 AC: 3619 AN: 3770

European-Finnish (FIN) AF: 0.993 AC: 1467 AN: 1478

Middle Eastern (MID) AF: 1.00 AC: 122 AN: 122

European-Non Finnish (NFE) AF: 0.999 AC: 20848 AN: 20874

Other (OTH) AF: 0.983 AC: 1692 AN: 1722

GnomAD4 genome AF: 0.965 AC: 147082 AN: 152348 Hom.: 71128 Cov.: 34 AF XY: 0.964 AC XY: 71840 AN XY: 74490

African (AFR) AF: 0.924 AC: 38417 AN: 41582

American (AMR) AF: 0.919 AC: 14058 AN: 15302

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

East Asian (EAS) AF: 0.903 AC: 4674 AN: 5174

South Asian (SAS) AF: 0.965 AC: 4658 AN: 4826

European-Finnish (FIN) AF: 0.995 AC: 10569 AN: 10624

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

European-Non Finnish (NFE) AF: 0.999 AC: 67979 AN: 68046

Other (OTH) AF: 0.971 AC: 2055 AN: 2116

Alfa AF: 0.969 Hom.: 11073

Bravo AF: 0.956

Asia WGS AF: 0.924 AC: 3214 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.8
DANN	Benign	0.95
PhyloP100		-0.18
PromoterAI		-0.055	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;