chr16-23641302-C-G

Variant names:

• chr16-23641302-C-G
• rs373698818
• NM_024675.4:c.-145G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024675.4(PALB2):​c.-145G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000397 in 1,008,450 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: 0.0000040 (0 hom.)
• Consequence: PALB2 NM_024675.4 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.88
• Publications: 0 publications found

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]

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]

ACMG classification

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=-0.62).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.-145G>C		5_prime_UTR_variant	Exon 1 of 13	ENST00000261584.9	NP_078951.2
DCTN5	NM_032486.4	c.-241C>G		upstream_gene_variant		ENST00000300087.7	NP_115875.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.-145G>C		5_prime_UTR_variant	Exon 1 of 13	1	NM_024675.4	ENSP00000261584.4
DCTN5	ENST00000300087.7	c.-241C>G		upstream_gene_variant		1	NM_032486.4	ENSP00000300087.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000397 AC: 4 AN: 1008450 Hom.: 0 Cov.: 13 AF XY: 0.00000394 AC XY: 2 AN XY: 507734

African (AFR) AF: 0.00 AC: 0 AN: 23664

American (AMR) AF: 0.00 AC: 0 AN: 29690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20654

East Asian (EAS) AF: 0.00 AC: 0 AN: 33828

South Asian (SAS) AF: 0.00 AC: 0 AN: 67996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3226

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 742406

Other (OTH) AF: 0.0000901 AC: 4 AN: 44388

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial cancer of breast Benign:1

May 13, 2019

Leiden Open Variation Database

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Benign	0.94
PhyloP100		1.9
PromoterAI		0.16	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs373698818; hg19: chr16-23652623;