rs975974

Positions:

• chr2-43713127-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_172069.4(PLEKHH2):​c.2460+744T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 138,976 control chromosomes in the GnomAD database, including 2,933 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (2933 hom., cov: 32)
• Consequence: PLEKHH2 NM_172069.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.617

Genes affected

PLEKHH2 (HGNC:30506): (pleckstrin homology, MyTH4 and FERM domain containing H2) Predicted to enable actin binding activity. Predicted to be involved in negative regulation of actin filament depolymerization. Located in several cellular components, including cytosol; lamellipodium; and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHH2	NM_172069.4	c.2460+744T>C		intron_variant		ENST00000282406.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHH2	ENST00000282406.9	c.2460+744T>C		intron_variant		1	NM_172069.4	P1
PLEKHH2	ENST00000405000.6	n.4386+744T>C		intron_variant, non_coding_transcript_variant		1
PLEKHH2	ENST00000405223.6	n.2540+744T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.198 AC: 27461 AN: 138916 Hom.: 2931 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.0321

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.154

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.202

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.198 AC: 27477 AN: 138976 Hom.: 2933 Cov.: 32 AF XY: 0.198 AC XY: 13481 AN XY: 68220

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.169

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.0324

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.306

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.203

Alfa AF: 0.198 Hom.: 1156

Bravo AF: 0.165

Asia WGS AF: 0.121 AC: 421 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.5
DANN	Benign	0.64

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: rs975974; hg19: chr2-43940266;