rs4935502

Variant names:

• chr10-54195684-T-G
• rs4935502
• NM_033056.4:c.1304A>C

Your query was ambiguous. Multiple possible variants found:

• chr10-54195684-T-G
• chr10-54195684-T-A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_001384140.1(PCDH15):​c.1304A>C​(p.Asp435Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,610,574 control chromosomes in the GnomAD database, including 39,899 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (3801 hom., cov: 32)
  • Exomes 𝑓: 0.18 (36098 hom.)
• Consequence: PCDH15 NM_001384140.1 missense, splice_region
• Scores: Splicing: ADA: 0.9938
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 7.99
• Publications: 55 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 10-54195684-T-G is Benign according to our data. Variant chr10-54195684-T-G is described in ClinVar as Benign. ClinVar VariationId is 46440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

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.1304A>C	p.Asp435Ala	missense splice_region	Exon 11 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.1304A>C	p.Asp435Ala	missense splice_region	Exon 11 of 38	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.1319A>C	p.Asp440Ala	missense splice_region	Exon 12 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.1304A>C	p.Asp435Ala	missense splice_region	Exon 11 of 33	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.1304A>C	p.Asp435Ala	missense splice_region	Exon 11 of 38	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.1304A>C	p.Asp435Ala	missense splice_region	Exon 11 of 35	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26747 AN: 152036 Hom.: 3799 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.843

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.176

GnomAD2 exomes AF: 0.240 AC: 60262 AN: 251270 AF XY: 0.240

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.843

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.178 AC: 258923 AN: 1458420 Hom.: 36098 Cov.: 30 AF XY: 0.182 AC XY: 132192 AN XY: 725766

African (AFR) AF: 0.130 AC: 4318 AN: 33304

American (AMR) AF: 0.280 AC: 12515 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3628 AN: 26116

East Asian (EAS) AF: 0.870 AC: 34508 AN: 39660

South Asian (SAS) AF: 0.341 AC: 29344 AN: 86152

European-Finnish (FIN) AF: 0.146 AC: 7789 AN: 53404

Middle Eastern (MID) AF: 0.202 AC: 1162 AN: 5758

European-Non Finnish (NFE) AF: 0.138 AC: 153501 AN: 1109056

Other (OTH) AF: 0.202 AC: 12158 AN: 60268

GnomAD4 genome AF: 0.176 AC: 26758 AN: 152154 Hom.: 3801 Cov.: 32 AF XY: 0.186 AC XY: 13838 AN XY: 74358

African (AFR) AF: 0.131 AC: 5424 AN: 41524

American (AMR) AF: 0.213 AC: 3248 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 470 AN: 3472

East Asian (EAS) AF: 0.843 AC: 4337 AN: 5142

South Asian (SAS) AF: 0.369 AC: 1782 AN: 4826

European-Finnish (FIN) AF: 0.143 AC: 1514 AN: 10590

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9432 AN: 67998

Other (OTH) AF: 0.180 AC: 381 AN: 2116

Alfa AF: 0.165 Hom.: 14052

Bravo AF: 0.182

TwinsUK AF: 0.129 AC: 478

ALSPAC AF: 0.143 AC: 551

ESP6500AA AF: 0.131 AC: 579

ESP6500EA AF: 0.132 AC: 1133

ExAC AF: 0.238 AC: 28895

Asia WGS AF: 0.575 AC: 1995 AN: 3478

EpiCase AF: 0.146

EpiControl AF: 0.145

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	3	Usher syndrome type 1F (3)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.054	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		8.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.21
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.87	P
Vest4		0.53
MPC		0.13
ClinPred		0.020	T
GERP RS		5.1
PromoterAI		-0.026	Neutral
Varity_R		0.23
gMVP		0.41
Mutation Taster		=55/45	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.95
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: rs4935502; hg19: chr10-55955444; COSMIC: COSV57312908;