rs11004439

Variant names:

• chr10-54664208-A-C
• rs11004439
• NM_033056.4:c.55T>G

Your query was ambiguous. Multiple possible variants found:

• chr10-54664208-A-C
• chr10-54664208-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001142763.2(PCDH15):​c.55T>G​(p.Ser19Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,610,862 control chromosomes in the GnomAD database, including 44,316 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S19T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.20 (3422 hom., cov: 31)
  • Exomes 𝑓: 0.23 (40894 hom.)
• Consequence: PCDH15 NM_001142763.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.188
• Publications: 40 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, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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=0.012873054).
• BP6: Variant 10-54664208-A-C is Benign according to our data. Variant chr10-54664208-A-C is described in ClinVar as Benign. ClinVar VariationId is 46504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142763.2. 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.55T>G	p.Ser19Ala	missense	Exon 2 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.55T>G	p.Ser19Ala	missense	Exon 2 of 38	NP_001371069.1
	PCDH15	NM_001142763.2		c.55T>G	p.Ser19Ala	missense	Exon 2 of 35	NP_001136235.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.55T>G	p.Ser19Ala	missense	Exon 2 of 33	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.55T>G	p.Ser19Ala	missense	Exon 2 of 38	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.55T>G	p.Ser19Ala	missense	Exon 2 of 35	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31001 AN: 151808 Hom.: 3424 Cov.: 31

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.243

GnomAD2 exomes AF: 0.221 AC: 55151 AN: 250098 AF XY: 0.218

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.293

Gnomad ASJ exome AF: 0.317

Gnomad EAS exome AF: 0.139

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.247

Gnomad OTH exome AF: 0.236

GnomAD4 exome AF: 0.232 AC: 338249 AN: 1458936 Hom.: 40894 Cov.: 33 AF XY: 0.230 AC XY: 167052 AN XY: 725862

African (AFR) AF: 0.141 AC: 4705 AN: 33388

American (AMR) AF: 0.287 AC: 12768 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 8182 AN: 26052

East Asian (EAS) AF: 0.118 AC: 4659 AN: 39628

South Asian (SAS) AF: 0.149 AC: 12809 AN: 86132

European-Finnish (FIN) AF: 0.149 AC: 7965 AN: 53338

Middle Eastern (MID) AF: 0.330 AC: 1902 AN: 5756

European-Non Finnish (NFE) AF: 0.245 AC: 271437 AN: 1109888

Other (OTH) AF: 0.229 AC: 13822 AN: 60242

GnomAD4 genome AF: 0.204 AC: 31010 AN: 151926 Hom.: 3422 Cov.: 31 AF XY: 0.199 AC XY: 14783 AN XY: 74290

African (AFR) AF: 0.140 AC: 5809 AN: 41504

American (AMR) AF: 0.245 AC: 3726 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1115 AN: 3462

East Asian (EAS) AF: 0.127 AC: 653 AN: 5160

South Asian (SAS) AF: 0.144 AC: 692 AN: 4822

European-Finnish (FIN) AF: 0.147 AC: 1559 AN: 10590

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.245 AC: 16628 AN: 67854

Other (OTH) AF: 0.241 AC: 508 AN: 2106

Alfa AF: 0.236 Hom.: 16815

Bravo AF: 0.217

TwinsUK AF: 0.244 AC: 904

ALSPAC AF: 0.232 AC: 893

ESP6500AA AF: 0.150 AC: 662

ESP6500EA AF: 0.250 AC: 2148

ExAC AF: 0.214 AC: 26012

Asia WGS AF: 0.125 AC: 437 AN: 3478

EpiCase AF: 0.257

EpiControl AF: 0.262

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Usher syndrome type 1F (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 23 (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.4
DANN	Benign	0.92
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.19
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.019
Sift	Benign	0.11	T
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.061
MPC		0.025
ClinPred		0.0012	T
GERP RS		0.64
Varity_R		0.062
gMVP		0.24
Mutation Taster		=299/1	polymorphism (auto)

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: rs11004439; hg19: chr10-56423968; COSMIC: COSV57279216;