5-141331554-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000517417.3(PCDHGA1):ā€‹c.870A>Cā€‹(p.Gln290His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,614,080 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 (ā˜…).

Frequency

Genomes: š‘“ 0.00020 ( 0 hom., cov: 32)
Exomes š‘“: 0.000016 ( 0 hom. )

Consequence

PCDHGA1
ENST00000517417.3 missense

Scores

1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.16
Variant links:
Genes affected
PCDHGA1 (HGNC:8696): (protocadherin gamma subfamily A, 1) This gene is a member of the protocadherin gamma gene cluster, one of three related clusters tandemly linked on chromosome five. These gene clusters have an immunoglobulin-like organization, suggesting that a novel mechanism may be involved in their regulation and expression. The gamma gene cluster includes 22 genes divided into 3 subfamilies. Subfamily A contains 12 genes, subfamily B contains 7 genes and 2 pseudogenes, and the more distantly related subfamily C contains 3 genes. The tandem array of 22 large, variable region exons are followed by a constant region, containing 3 exons shared by all genes in the cluster. Each variable region exon encodes the extracellular region, which includes 6 cadherin ectodomains and a transmembrane region. The constant region exons encode the common cytoplasmic region. These neural cadherin-like cell adhesion proteins most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been described for the gamma cluster genes. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.03572586).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PCDHGA1NM_018912.3 linkuse as main transcriptc.870A>C p.Gln290His missense_variant 1/4 ENST00000517417.3 NP_061735.1
PCDHGA1NM_031993.2 linkuse as main transcriptc.870A>C p.Gln290His missense_variant 1/1 NP_114382.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PCDHGA1ENST00000517417.3 linkuse as main transcriptc.870A>C p.Gln290His missense_variant 1/41 NM_018912.3 ENSP00000431083 P1Q9Y5H4-1
PCDHGA1ENST00000378105.4 linkuse as main transcriptc.870A>C p.Gln290His missense_variant 1/1 ENSP00000367345 Q9Y5H4-2

Frequencies

GnomAD3 genomes
AF:
0.000204
AC:
31
AN:
152240
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000748
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251170
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135762
show subpopulations
Gnomad AFR exome
AF:
0.000370
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000157
AC:
23
AN:
1461840
Hom.:
0
Cov.:
37
AF XY:
0.0000124
AC XY:
9
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.000627
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.000204
AC:
31
AN:
152240
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.000748
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000563
Hom.:
0
Bravo
AF:
0.000155
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 12, 2021The c.870A>C (p.Q290H) alteration is located in exon 1 (coding exon 1) of the PCDHGA1 gene. This alteration results from a A to C substitution at nucleotide position 870, causing the glutamine (Q) at amino acid position 290 to be replaced by a histidine (H). 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
0.13
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
5.7
DANN
Benign
0.55
DEOGEN2
Benign
0.27
.;T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.051
N
LIST_S2
Benign
0.29
T;T
M_CAP
Benign
0.0054
T
MetaRNN
Benign
0.036
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.95
L;L
MutationTaster
Benign
1.0
N;N
PROVEAN
Uncertain
-2.6
D;D
REVEL
Benign
0.029
Sift
Benign
0.073
T;T
Sift4G
Benign
0.16
T;T
Polyphen
0.046
B;B
Vest4
0.099
MutPred
0.41
Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP
0.29
MPC
0.29
ClinPred
0.15
T
GERP RS
-7.0
Varity_R
0.12
gMVP
0.090

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs772943752; hg19: chr5-140711121; API