chr10-53866827-C-T

Variant names:

• chr10-53866827-C-T
• rs147835286
• NM_033056.4:c.3532G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001384140.1(PCDH15):​c.3532G>A​(p.Val1178Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,612,174 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (21 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.24
• Publications: 6 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059161186).
• BP6: Variant 10-53866827-C-T is Benign according to our data. Variant chr10-53866827-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00775 (1176/151684) while in subpopulation AFR AF = 0.0267 (1104/41318). AF 95% confidence interval is 0.0254. There are 18 homozygotes in GnomAd4. There are 552 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384140.1. 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
	PCDH15	NM_033056.4	MANE Plus Clinical	c.3532G>A	p.Val1178Ile	missense	Exon 27 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.3532G>A	p.Val1178Ile	missense	Exon 27 of 38	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.3547G>A	p.Val1183Ile	missense	Exon 28 of 35	NP_001136235.1	A2A3D8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.3532G>A	p.Val1178Ile	missense	Exon 27 of 33	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.3532G>A	p.Val1178Ile	missense	Exon 27 of 38	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.3553G>A	p.Val1185Ile	missense	Exon 28 of 35	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.00773 AC: 1172 AN: 151568 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00381

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: 0.0000883

Gnomad OTH AF: 0.00386

GnomAD2 exomes AF: 0.00195 AC: 489 AN: 251186 AF XY: 0.00137

Gnomad AFR exome AF: 0.0268

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000752 AC: 1098 AN: 1460490 Hom.: 21 Cov.: 32 AF XY: 0.000588 AC XY: 427 AN XY: 726660

African (AFR) AF: 0.0275 AC: 918 AN: 33430

American (AMR) AF: 0.00166 AC: 74 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1110832

Other (OTH) AF: 0.00144 AC: 87 AN: 60336

GnomAD4 genome AF: 0.00775 AC: 1176 AN: 151684 Hom.: 18 Cov.: 32 AF XY: 0.00745 AC XY: 552 AN XY: 74098

African (AFR) AF: 0.0267 AC: 1104 AN: 41318

American (AMR) AF: 0.00381 AC: 58 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67944

Other (OTH) AF: 0.00382 AC: 8 AN: 2094

Alfa AF: 0.00262 Hom.: 14

Bravo AF: 0.00880

ESP6500AA AF: 0.0266 AC: 117

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00241 AC: 292

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.063
Sift	Benign	0.28	T
Sift4G	Uncertain	0.058	T
Polyphen		0.022	B
Vest4		0.24
MVP		0.47
MPC		0.037
ClinPred		0.017	T
GERP RS		4.9
Varity_R		0.062
gMVP		0.13
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs147835286; hg19: chr10-55626587;