dbSNP rs515726054: PALB2:c.-194C>T (chr16-23641351-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024675.4(PALB2):c.-194C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000118 in 844,900 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.0000012 ( 0 hom. )

Consequence

PALB2
NM_024675.4 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.680

Publications

0 publications found

Variant links:

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]

PALB2 links:

DCTN5 (HGNC:24594): (dynactin subunit 5) This gene encodes a subunit of dynactin, a component of the cytoplasmic dynein motor machinery involved in minus-end-directed transport. The encoded protein is a component of the pointed-end subcomplex and is thought to bind membranous cargo. A pseudogene of this gene is located on the long arm of chromosome 1. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

DCTN5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024675.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PALB2	NM_024675.4	MANE Select	c.-194C>T	upstream_gene	N/A	NP_078951.2
DCTN5	NM_032486.4	MANE Select	c.-192G>A	upstream_gene	N/A	NP_115875.1
PALB2	NM_001407296.1		c.-194C>T	upstream_gene	N/A	NP_001394225.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PALB2	ENST00000261584.9	TSL:1 MANE Select	c.-194C>T	upstream_gene	N/A	ENSP00000261584.4
DCTN5	ENST00000300087.7	TSL:1 MANE Select	c.-192G>A	upstream_gene	N/A	ENSP00000300087.2
PALB2	ENST00000568219.5	TSL:1	c.-1062C>T	upstream_gene	N/A	ENSP00000454703.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000118

AC:

AN:

844900

Hom.:

Cov.:

AF XY:

0.00000233

AC XY:

AN XY:

429680

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

20336

American (AMR)

AF:

0.00

AC:

AN:

26688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18144

East Asian (EAS)

AF:

0.00

AC:

AN:

33014

South Asian (SAS)

AF:

0.00

AC:

AN:

59596

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2860

European-Non Finnish (NFE)

AF:

0.00000165

AC:

AN:

605590

Other (OTH)

AF:

0.00

AC:

AN:

39060

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

1.6

(source)

DANN

Benign

0.87

PhyloP100

-0.68

PromoterAI

-0.15

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over