21-39929026-A-T

Variant names:

• chr21-39929026-A-T
• rs777175019
• NM_006198.3:c.104A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006198.3(PCP4):​c.104A>T​(p.Asp35Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,114 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D35G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PCP4 NM_006198.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.84
• Publications: 0 publications found

Genes affected

PCP4 (HGNC:8742): (Purkinje cell protein 4) Enables calcium ion binding activity and calmodulin binding activity. Involved in calmodulin dependent kinase signaling pathway and positive regulation of neuron differentiation. Located in cytosol and nucleus. Part of protein-containing complex. Biomarker of Huntington's disease and leiomyoma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006198.3. 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
	PCP4	NM_006198.3	MANE Select	c.104A>T	p.Asp35Val	missense	Exon 3 of 3	NP_006189.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCP4	ENST00000328619.10	TSL:1 MANE Select	c.104A>T	p.Asp35Val	missense	Exon 3 of 3	ENSP00000329403.5	P48539
	PCP4	ENST00000462224.5	TSL:2	n.*153A>T		non_coding_transcript_exon	Exon 4 of 4	ENSP00000433172.1	F6SSA2
	PCP4	ENST00000467565.1	TSL:5	n.216A>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461114 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726890

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111512

Other (OTH) AF: 0.00 AC: 0 AN: 60370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.46	T
PhyloP100		6.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.26
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.12	T
Polyphen		0.98	D
Vest4		0.56
MutPred		0.27		Loss of helix (P = 0.079)
MVP		0.24
MPC		0.47
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.47
gMVP		0.87
Mutation Taster		=38/62	disease causing

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: rs777175019; hg19: chr21-41300951;