14-69524240-T-C

Position:

• chr14-69524240-T-C

Variant summary

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

The NM_001161498.2(PLEKHD1):​c.662T>C​(p.Leu221Pro) 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: PLEKHD1 NM_001161498.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.38

Genes affected

PLEKHD1 (HGNC:20148): (pleckstrin homology and coiled-coil domain containing D1)

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=0.25695708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHD1	NM_001161498.2	c.662T>C	p.Leu221Pro	missense_variant	8/13	ENST00000322564.9	NP_001154970.1
PLEKHD1	XM_017021290.1	c.368T>C	p.Leu123Pro	missense_variant	8/13		XP_016876779.1
PLEKHD1	XM_011536762.2	c.281T>C	p.Leu94Pro	missense_variant	5/10		XP_011535064.1
PLEKHD1	XM_011536763.2	c.113T>C	p.Leu38Pro	missense_variant	3/8		XP_011535065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHD1	ENST00000322564.9	c.662T>C	p.Leu221Pro	missense_variant	8/13	1	NM_001161498.2	ENSP00000317175.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Jan 26, 2022

The c.662T>C (p.L221P) alteration is located in exon 8 (coding exon 8) of the PLEKHD1 gene. This alteration results from a T to C substitution at nucleotide position 662, causing the leucine (L) at amino acid position 221 to be replaced by a proline (P). 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	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.12
Sift	Benign	0.062	T
Sift4G	Benign	0.28	T
Vest4		0.52
MutPred		0.32		Loss of helix (P = 0.0444);
MVP		0.15
ClinPred		0.84	D
GERP RS		5.5
Varity_R		0.60
gMVP		0.59

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: chr14-69990957;