NM_001161498.2:c.719C>G

Variant names:

• chr14-69524297-C-G
• rs780185148
• NM_001161498.2:c.719C>G

Variant summary

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

The NM_001161498.2(PLEKHD1):​c.719C>G​(p.Thr240Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,399,296 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. T240M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PLEKHD1 NM_001161498.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.13

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHD1	NM_001161498.2	c.719C>G	p.Thr240Arg	missense_variant	Exon 8 of 13	ENST00000322564.9	NP_001154970.1
PLEKHD1	XM_017021290.1	c.425C>G	p.Thr142Arg	missense_variant	Exon 8 of 13		XP_016876779.1
PLEKHD1	XM_011536762.2	c.338C>G	p.Thr113Arg	missense_variant	Exon 5 of 10		XP_011535064.1
PLEKHD1	XM_011536763.2	c.170C>G	p.Thr57Arg	missense_variant	Exon 3 of 8		XP_011535065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHD1	ENST00000322564.9	c.719C>G	p.Thr240Arg	missense_variant	Exon 8 of 13	1	NM_001161498.2	ENSP00000317175.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399296 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 690176

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: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.20	T
Vest4		0.76
MutPred		0.27		Gain of MoRF binding (P = 0.0214);
MVP		0.048
ClinPred		0.92	D
GERP RS		5.6
Varity_R		0.56
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs780185148; hg19: chr14-69991014;