8-101666577-C-T

Position:

• chr8-101666577-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_024915.4(GRHL2):​c.1764-12C>T variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001415
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.02

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.1764-12C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2	c.1716-12C>T		splice_polypyrimidine_tract_variant, intron_variant			NP_001317522.1
GRHL2	XM_011517306.4	c.1716-12C>T		splice_polypyrimidine_tract_variant, intron_variant			XP_011515608.1
GRHL2	XM_011517307.4	c.1763+2059C>T		intron_variant			XP_011515609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.1764-12C>T		splice_polypyrimidine_tract_variant, intron_variant			NM_024915.4	ENSP00000495564	P1
GRHL2	ENST00000395927.1	c.1716-12C>T		splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000379260

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251028 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135654

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000236

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000773

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs371424751; hg19: chr8-102678805;