2-205104440-C-A

Variant names:

• chr2-205104440-C-A
• rs1703051369
• NM_001302769.2:c.519C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001302769.2(PARD3B):​c.519C>A​(p.Asn173Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PARD3B NM_001302769.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.366

Genes affected

PARD3B (HGNC:14446): (par-3 family cell polarity regulator beta) Predicted to enable phosphatidylinositol binding activity. Predicted to be involved in several processes, including establishment of cell polarity; establishment of centrosome localization; and establishment or maintenance of epithelial cell apical/basal polarity. Located in cell junction. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.058559507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARD3B	NM_001302769.2	c.519C>A	p.Asn173Lys	missense_variant	Exon 5 of 23	ENST00000406610.7	NP_001289698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARD3B	ENST00000406610.7	c.519C>A	p.Asn173Lys	missense_variant	Exon 5 of 23	1	NM_001302769.2	ENSP00000385848.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.519C>A (p.N173K) alteration is located in exon 5 (coding exon 5) of the PARD3B gene. This alteration results from a C to A substitution at nucleotide position 519, causing the asparagine (N) at amino acid position 173 to be replaced by a lysine (K). 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	0.12
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.0081	T;T;.;.;.;.;.;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.62	T;T;T;T;T;T;T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.059	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L;.;L;L;L;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;.;N;N;N;.;.;.
REVEL	Benign	0.058
Sift	Benign	0.068	T;.;T;T;T;.;.;.
Sift4G	Benign	0.55	T;T;T;T;T;T;T;T
Polyphen		0.054	B;.;B;.;B;.;.;.
Vest4		0.12
MutPred		0.30		Gain of ubiquitination at N173 (P = 0.0045);Gain of ubiquitination at N173 (P = 0.0045);Gain of ubiquitination at N173 (P = 0.0045);Gain of ubiquitination at N173 (P = 0.0045);Gain of ubiquitination at N173 (P = 0.0045);.;.;.;
MVP		0.23
MPC		0.024
ClinPred		0.033	T
GERP RS		-2.4
Varity_R		0.079
gMVP		0.14

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: rs1703051369; hg19: chr2-205969164; COSMIC: COSV100591684;