3-111884693-A-C

Variant summary

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

The NM_001134438.2(PHLDB2):c.616A>C(p.Lys206Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHLDB2 NM_001134438.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.69

Genes affected

PHLDB2 (HGNC:29573): (pleckstrin homology like domain family B member 2) Enables cadherin binding activity. Involved in several processes, including negative regulation of focal adhesion assembly; regulation of cytoskeleton organization; and regulation of embryonic development. Located in several cellular components, including basal cortex; cell leading edge; and intermediate filament cytoskeleton. Colocalizes with focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

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=0.25710994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHLDB2	NM_001134438.2	c.616A>C	p.Lys206Gln	missense_variant	2/18	ENST00000431670.7
PHLDB2	NM_001134439.2	c.616A>C	p.Lys206Gln	missense_variant	2/18
PHLDB2	NM_001134437.2	c.697A>C	p.Lys233Gln	missense_variant	3/18
PHLDB2	NM_145753.2	c.616A>C	p.Lys206Gln	missense_variant	2/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHLDB2	ENST00000431670.7	c.616A>C	p.Lys206Gln	missense_variant	2/18	1	NM_001134438.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

May 04, 2022

The c.616A>C (p.K206Q) alteration is located in exon 2 (coding exon 1) of the PHLDB2 gene. This alteration results from a A to C substitution at nucleotide position 616, causing the lysine (K) at amino acid position 206 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.94	D;D;.;D;D;D;D;.
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationTaster	Benign	0.64	D;D;N;N;N;N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N;N
REVEL	Benign	0.096
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D
Sift4G	Benign	0.087	T;T;T;T;T;T;T;T
Polyphen		0.42	B;D;D;.;D;D;D;D
Vest4		0.42
MutPred		0.32		.;Loss of methylation at K206 (P = 0.0058);Loss of methylation at K206 (P = 0.0058);Loss of methylation at K206 (P = 0.0058);Loss of methylation at K206 (P = 0.0058);Loss of methylation at K206 (P = 0.0058);Loss of methylation at K206 (P = 0.0058);Loss of methylation at K206 (P = 0.0058);
MVP		0.64
MPC		0.18
ClinPred		0.93	D
GERP RS		5.6
Varity_R		0.36
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-111603540;