chr8-101666577-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_024915.4(GRHL2):c.1764-12C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000758 in 1,529,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

GRHL2
NM_024915.4 intron

Scores

Splicing: ADA: 0.0001986

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -3.02

Publications

1 publications found

Variant links:

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

GRHL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 8-101666577-C-G is Benign according to our data. Variant chr8-101666577-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228732.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000719 (99/1377384) while in subpopulation MID AF = 0.00124 (7/5634). AF 95% confidence interval is 0.000582. There are 0 homozygotes in GnomAdExome4. There are 51 alleles in the male GnomAdExome4 subpopulation. Median coverage is 24. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
GRHL2	NM_024915.4 link	c.1764-12C>G	intron_variant	Intron 15 of 15	ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2 link	c.1716-12C>G	intron_variant	Intron 15 of 15		NP_001317522.1
GRHL2	NM_001440448.1 link	c.1716-12C>G	intron_variant	Intron 15 of 15		NP_001427377.1
GRHL2	NM_001440447.1 link	c.1763+2059C>G	intron_variant	Intron 15 of 15		NP_001427376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1 link	c.1764-12C>G		intron_variant	Intron 15 of 15		NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000395927.1 link	c.1716-12C>G		intron_variant	Intron 15 of 15	2		ENSP00000379260.1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000104

AC:

AN:

251028

AF XY:

0.0000958

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000719

AC:

AN:

1377384

Hom.:

Cov.:

AF XY:

0.0000739

AC XY:

AN XY:

690308

show subpopulations

African (AFR)

AF:

0.000347

AC:

AN:

31726

American (AMR)

AF:

0.000202

AC:

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.000117

AC:

AN:

25622

East Asian (EAS)

AF:

0.000153

AC:

AN:

39268

South Asian (SAS)

AF:

0.000177

AC:

AN:

84578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00124

AC:

AN:

5634

European-Non Finnish (NFE)

AF:

0.0000348

AC:

AN:

1035014

Other (OTH)

AF:

0.000209

AC:

AN:

57538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000112

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41532

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.000415

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000170

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 18, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1764-12C>G variant in GRHL2 has been reported by our laboratory in one ind ividual with hearing loss. This variant was identified in 5/16156 South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs371424751); however, its frequency is not high enough to rule out a pathogenic role. This variant is located in the 3' splice region. Computational tools do not suggest an impact to splicing; however, this information is not pr edictive enough to rule out pathogenicity. In summary, the clinical significance of the c.1764-12C>G variant is uncertain. -

not provided

Benign:1

Apr 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.012

(source)

DANN

Benign

0.33

PhyloP100

-3.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00020

dbscSNV1_RF

Benign

0.10

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over