rs567706422

Variant names:

• chr16-23641146-A-G
• rs567706422
• NM_024675.4:c.12T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-23641146-A-G
• chr16-23641146-A-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_024675.4(PALB2):​c.12T>C​(p.Pro4Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,613,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P4P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: PALB2 NM_024675.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 0.261
• Publications: 4 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 16-23641146-A-G is Benign according to our data. Variant chr16-23641146-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 136128.
• BP7: Synonymous conserved (PhyloP=0.261 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	NM_024675.4	MANE Select	c.12T>C	p.Pro4Pro	synonymous	Exon 1 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.12T>C	p.Pro4Pro	synonymous	Exon 1 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.12T>C	p.Pro4Pro	synonymous	Exon 1 of 12	NP_001394226.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.12T>C	p.Pro4Pro	synonymous	Exon 1 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.-857T>C		5_prime_UTR	Exon 1 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000970391.1		c.12T>C	p.Pro4Pro	synonymous	Exon 1 of 12	ENSP00000640450.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000607 AC: 15 AN: 247248 AF XY: 0.0000745

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000248 AC: 363 AN: 1460930 Hom.: 0 Cov.: 31 AF XY: 0.000233 AC XY: 169 AN XY: 726724

African (AFR) AF: 0.0000299 AC: 1 AN: 33454

American (AMR) AF: 0.0000224 AC: 1 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5472

European-Non Finnish (NFE) AF: 0.000320 AC: 356 AN: 1111816

Other (OTH) AF: 0.0000829 AC: 5 AN: 60288

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74388

African (AFR) AF: 0.0000241 AC: 1 AN: 41490

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67976

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.0000718

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	Familial cancer of breast (4)
-	-	4	not specified (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	not provided (2)
-	1	-	Fanconi anemia complementation group N (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	13
DANN	Benign	0.76
PhyloP100		0.26
PromoterAI		0.0042	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs567706422; hg19: chr16-23652467;