20-50749718-A-G

Position:

• chr20-50749718-A-G

Variant summary

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

The NM_032521.3(PARD6B):​c.349A>G​(p.Thr117Ala) 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 1,461,024 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PARD6B NM_032521.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26

Genes affected

PARD6B (HGNC:16245): (par-6 family cell polarity regulator beta) This gene is a member of the PAR6 family and encodes a protein with a PSD95/Discs-large/ZO1 (PDZ) domain, an OPR domain and a semi-Cdc42/Rac interactive binding (CRIB) domain. This cytoplasmic protein is involved in asymmetrical cell division and cell polarization processes as a member of a multi-protein complex. [provided by RefSeq, Jul 2008]

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=0.052027255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARD6B	NM_032521.3	c.349A>G	p.Thr117Ala	missense_variant	3/3	ENST00000371610.7	NP_115910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARD6B	ENST00000371610.7	c.349A>G	p.Thr117Ala	missense_variant	3/3	1	NM_032521.3	ENSP00000360672.2
PARD6B	ENST00000396039.1	c.290-6967A>G		intron_variant		1		ENSP00000379354.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461024 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726812

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.: 32

Bravo AF: 0.00000378

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

Feb 06, 2024

The c.349A>G (p.T117A) alteration is located in exon 3 (coding exon 3) of the PARD6B gene. This alteration results from a A to G substitution at nucleotide position 349, causing the threonine (T) at amino acid position 117 to be replaced by an alanine (A). 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	0.062
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Benign	0.60
DEOGEN2	Benign	0.0060	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.0	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.042
Sift	Benign	0.30	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.013
MutPred		0.37		Loss of methylation at K112 (P = 0.0558);
MVP		0.29
MPC		0.31
ClinPred		0.16	T
GERP RS		4.9
Varity_R		0.026
gMVP		0.37

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: rs2087588948; hg19: chr20-49366255;