rs138200248

Variant names:

• chr16-23641315-C-G
• rs138200248
• ENST00000697383.1:c.-158G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-23641315-C-G
• chr16-23641315-C-A
• chr16-23641315-C-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The ENST00000697383.1(PALB2):​c.-158G>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 0.00547 in 1,093,920 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene PALB2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0059 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (45 hom.)
• Consequence: PALB2 ENST00000697383.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.439
• Publications: 2 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

Specifications for PALB2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 16-23641315-C-G is Benign according to our data. Variant chr16-23641315-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126571.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0059 (899/152344) while in subpopulation NFE AF = 0.00735 (500/68034). AF 95% confidence interval is 0.00682. There are 6 homozygotes in GnomAd4. There are 500 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000697383.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	NM_024675.4	MANE Select	c.-158G>C		upstream_gene	N/A	NP_078951.2
	DCTN5	NM_032486.4	MANE Select	c.-228C>G		upstream_gene	N/A	NP_115875.1	Q9BTE1-1
	PALB2	NM_001407296.1		c.-158G>C		upstream_gene	N/A	NP_001394225.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000697383.1		c.-158G>C		5_prime_UTR	Exon 1 of 9	ENSP00000513289.1	A0A8V8TLC8
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.-158G>C		upstream_gene	N/A	ENSP00000261584.4	Q86YC2
	DCTN5	ENST00000300087.7	TSL:1 MANE Select	c.-228C>G		upstream_gene	N/A	ENSP00000300087.2	Q9BTE1-1

Frequencies

GnomAD3 genomes AF: 0.00591 AC: 899 AN: 152226 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0326

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00735

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00540 AC: 5087 AN: 941576 Hom.: 45 Cov.: 12 AF XY: 0.00526 AC XY: 2506 AN XY: 475974

African (AFR) AF: 0.000670 AC: 15 AN: 22380

American (AMR) AF: 0.000938 AC: 27 AN: 28774

Ashkenazi Jewish (ASJ) AF: 0.00281 AC: 55 AN: 19584

East Asian (EAS) AF: 0.00 AC: 0 AN: 33494

South Asian (SAS) AF: 0.00 AC: 0 AN: 64840

European-Finnish (FIN) AF: 0.0298 AC: 1220 AN: 40962

Middle Eastern (MID) AF: 0.000322 AC: 1 AN: 3110

European-Non Finnish (NFE) AF: 0.00524 AC: 3596 AN: 686282

Other (OTH) AF: 0.00410 AC: 173 AN: 42150

GnomAD4 genome AF: 0.00590 AC: 899 AN: 152344 Hom.: 6 Cov.: 32 AF XY: 0.00671 AC XY: 500 AN XY: 74496

African (AFR) AF: 0.000649 AC: 27 AN: 41590

American (AMR) AF: 0.000718 AC: 11 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0326 AC: 346 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00735 AC: 500 AN: 68034

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00723 Hom.: 2

Bravo AF: 0.00292

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Familial cancer of breast (1)
-	1	-	Fanconi anemia complementation group N (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.71
PhyloP100		0.44
PromoterAI		0.28	Neutral

Splicing

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

Other links and lift over

dbSNP: rs138200248; hg19: chr16-23652636;