chr16-23629204-C-A

Variant names:

• chr16-23629204-C-A
• NM_024675.4:c.2586G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_024675.4(PALB2):​c.2586G>T​(p.Lys862Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000657 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PALB2 NM_024675.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.04

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.2586G>T	p.Lys862Asn	missense_variant, splice_region_variant	Exon 6 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2586G>T	p.Lys862Asn	missense_variant, splice_region_variant	Exon 6 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.6	.;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	.;D
Vest4		0.60
MutPred		0.26		.;Loss of ubiquitination at K862 (P = 0.0039);
MVP		0.78
MPC		0.36
ClinPred		0.98	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: 0

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: chr16-23640525;