chr8-101492563-C-T

Variant names:

• chr8-101492563-C-T
• rs141699759
• NM_024915.4:c.-207C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_024915.4(GRHL2):​c.-207C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 669,400 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0052 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (2 hom.)
• Consequence: GRHL2 NM_024915.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.11
• 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]

ENSG00000293625 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 8-101492563-C-T is Benign according to our data. Variant chr8-101492563-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1187735.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00518 (789/152352) while in subpopulation AFR AF = 0.0176 (732/41580). AF 95% confidence interval is 0.0165. There are 9 homozygotes in GnomAd4. There are 385 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR,Unknown gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2	NM_024915.4	MANE Select	c.-207C>T		5_prime_UTR	Exon 1 of 16	NP_079191.2	Q6ISB3-1
	GRHL2	NM_001330593.2		c.-315C>T		5_prime_UTR	Exon 1 of 16	NP_001317522.1	Q6ISB3-2
	GRHL2	NM_001440448.1		c.-52C>T		5_prime_UTR	Exon 1 of 16	NP_001427377.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2	ENST00000646743.1	MANE Select	c.-207C>T		5_prime_UTR	Exon 1 of 16	ENSP00000495564.1	Q6ISB3-1
	GRHL2	ENST00000472106.2	TSL:1	n.122C>T		non_coding_transcript_exon	Exon 1 of 2
	GRHL2	ENST00000521085.1	TSL:3	c.-92C>T		5_prime_UTR	Exon 1 of 2	ENSP00000430473.1

Frequencies

GnomAD3 genomes AF: 0.00516 AC: 785 AN: 152234 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00320

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000615 AC: 318 AN: 517048 Hom.: 2 Cov.: 4 AF XY: 0.000514 AC XY: 142 AN XY: 276008

African (AFR) AF: 0.0160 AC: 234 AN: 14658

American (AMR) AF: 0.00114 AC: 35 AN: 30750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16744

East Asian (EAS) AF: 0.00 AC: 0 AN: 31624

South Asian (SAS) AF: 0.0000187 AC: 1 AN: 53516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43092

Middle Eastern (MID) AF: 0.00130 AC: 3 AN: 2312

European-Non Finnish (NFE) AF: 0.0000169 AC: 5 AN: 295800

Other (OTH) AF: 0.00140 AC: 40 AN: 28552

GnomAD4 genome AF: 0.00518 AC: 789 AN: 152352 Hom.: 9 Cov.: 33 AF XY: 0.00517 AC XY: 385 AN XY: 74504

African (AFR) AF: 0.0176 AC: 732 AN: 41580

American (AMR) AF: 0.00320 AC: 49 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000615 Hom.: 0

Bravo AF: 0.00602

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely 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	-0.36
CADD	Benign	18
DANN	Benign	0.96
PhyloP100		1.1
PromoterAI		0.0035	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs141699759; hg19: chr8-102504791;