Genetic Variant NM_033056.4:c.5287_5292delGCTCCT (chr10-53822433-GAGGAGC-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_033056.4(PCDH15):c.5287_5292delGCTCCT(p.Ala1763_Pro1764del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000768 in 1,588,994 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 2 hom. )

Consequence

PCDH15
NM_033056.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:7

Conservation

PhyloP100: 4.46

Publications

2 publications found

Variant links:

Genes affected

PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

PCDH15 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 23
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
Usher syndrome type 1
Inheritance: AR, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Usher syndrome type 1F
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

PCDH15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_033056.4

BP6

Variant 10-53822433-GAGGAGC-G is Benign according to our data. Variant chr10-53822433-GAGGAGC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46493.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00101 (152/151192) while in subpopulation EAS AF = 0.00854 (44/5154). AF 95% confidence interval is 0.00654. There are 0 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033056.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCDH15	NM_033056.4	MANE Plus Clinical	c.5287_5292delGCTCCT	p.Ala1763_Pro1764del	conservative_inframe_deletion	Exon 33 of 33	NP_149045.3
PCDH15	NM_001384140.1	MANE Select	c.4368-2209_4368-2204delGCTCCT		intron	N/A	NP_001371069.1	Q96QU1-7
PCDH15	NM_001142763.2		c.5308_5313delGCTCCT	p.Ala1770_Pro1771del	conservative_inframe_deletion	Exon 35 of 35	NP_001136235.1	A2A3D8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.5287_5292delGCTCCT	p.Ala1763_Pro1764del	conservative_inframe_deletion	Exon 33 of 33	ENSP00000322604.6	Q96QU1-1
PCDH15	ENST00000644397.2	MANE Select	c.4368-2209_4368-2204delGCTCCT		intron	N/A	ENSP00000495195.1	Q96QU1-7
PCDH15	ENST00000395445.6	TSL:1	c.4388+4954_4388+4959delGCTCCT		intron	N/A	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

152

AN:

151074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00100

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000922

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00852

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000621

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.00103

AC:

216

AN:

209224

AF XY:

0.000977

show subpopulations

Gnomad AFR exome

AF:

0.00121

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.000107

Gnomad EAS exome

AF:

0.00503

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000678

Gnomad OTH exome

AF:

0.000917

GnomAD4 exome

AF:

0.000743

AC:

1068

AN:

1437802

Hom.:

AF XY:

0.000774

AC XY:

552

AN XY:

713558

show subpopulations

African (AFR)

AF:

0.00112

AC:

AN:

32130

American (AMR)

AF:

0.00101

AC:

AN:

41668

Ashkenazi Jewish (ASJ)

AF:

0.0000774

AC:

AN:

25856

East Asian (EAS)

AF:

0.00472

AC:

178

AN:

37700

South Asian (SAS)

AF:

0.00113

AC:

AN:

83980

European-Finnish (FIN)

AF:

0.0000193

AC:

AN:

51702

Middle Eastern (MID)

AF:

0.00317

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.000570

AC:

627

AN:

1099566

Other (OTH)

AF:

0.00116

AC:

AN:

59530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

132

197

263

329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00101

AC:

152

AN:

151192

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

73940

show subpopulations

African (AFR)

AF:

0.000999

AC:

AN:

41042

American (AMR)

AF:

0.000921

AC:

AN:

15202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00854

AC:

AN:

5154

South Asian (SAS)

AF:

0.00167

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000621

AC:

AN:

67668

Other (OTH)

AF:

0.000476

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.00

Hom.:

Bravo

AF:

0.00105

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Usher syndrome type 1F (2)

Hearing loss, autosomal recessive (1)

not specified (1)

PCDH15-related disorder (1)

Retinitis pigmentosa-deafness syndrome (1)

Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.5

Mutation Taster

=173/27

polymorphism

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over