8-101666577-C-T

Variant names:

• chr8-101666577-C-T
• rs371424751
• NM_024915.4:c.1764-12C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_024915.4(GRHL2):​c.1764-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000799 in 1,377,384 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000080 (0 hom.)
• Consequence: GRHL2 NM_024915.4 intron
• Scores: Splicing: ADA: 0.00001415
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.02
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024915.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2	NM_024915.4	MANE Select	c.1764-12C>T		intron	N/A	NP_079191.2
	GRHL2	NM_001330593.2		c.1716-12C>T		intron	N/A	NP_001317522.1
	GRHL2	NM_001440448.1		c.1716-12C>T		intron	N/A	NP_001427377.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2	ENST00000646743.1	MANE Select	c.1764-12C>T		intron	N/A	ENSP00000495564.1
	GRHL2	ENST00000395927.1	TSL:2	c.1716-12C>T		intron	N/A	ENSP00000379260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251028 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000799 AC: 11 AN: 1377384 Hom.: 0 Cov.: 24 AF XY: 0.00000579 AC XY: 4 AN XY: 690308

African (AFR) AF: 0.00 AC: 0 AN: 31726

American (AMR) AF: 0.0000224 AC: 1 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25622

East Asian (EAS) AF: 0.00 AC: 0 AN: 39268

South Asian (SAS) AF: 0.0000236 AC: 2 AN: 84578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.00000773 AC: 8 AN: 1035014

Other (OTH) AF: 0.00 AC: 0 AN: 57538

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.028
DANN	Benign	0.56
PhyloP100		-3.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0040
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: rs371424751; hg19: chr8-102678805;