5-140786858-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018900.4(PCDHA1):c.568A>C(p.Lys190Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PCDHA1 NM_018900.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80

Genes affected

PCDHA1 (HGNC:8663): (protocadherin alpha 1) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.142775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHA1	NM_018900.4	c.568A>C	p.Lys190Gln	missense_variant	1/4	ENST00000504120.4
PCDHA1	NM_031410.2	c.568A>C	p.Lys190Gln	missense_variant	1/1
PCDHA1	NM_031411.3	c.568A>C	p.Lys190Gln	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA1	ENST00000504120.4	c.568A>C	p.Lys190Gln	missense_variant	1/4	1	NM_018900.4	P1
PCDHA1	ENST00000394633.7	c.568A>C	p.Lys190Gln	missense_variant	1/4	1
	ENST00000655235.1	n.2654T>G		non_coding_transcript_exon_variant	2/2
PCDHA1	ENST00000378133.4	c.568A>C	p.Lys190Gln	missense_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251062 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461824 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2021

The c.568A>C (p.K190Q) alteration is located in exon 1 (coding exon 1) of the PCDHA1 gene. This alteration results from a A to C substitution at nucleotide position 568, causing the lysine (K) at amino acid position 190 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	20
Dann	Benign	0.87
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.12	T;T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.094	T;T;T
Sift4G	Benign	0.061	T;T;T
Polyphen		0.50	P;P;B
Vest4		0.15
MutPred		0.37		Loss of ubiquitination at K190 (P = 0.0134);Loss of ubiquitination at K190 (P = 0.0134);Loss of ubiquitination at K190 (P = 0.0134);
MVP		0.32
MPC		0.38
ClinPred		0.081	T
GERP RS		-0.47
Varity_R		0.11
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs782230479; hg19: chr5-140166443;