rs1806729

Variant names:

• chr4-168511690-G-A
• rs1806729
• NM_001166108.2:c.186G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001166108.2(PALLD):​c.186G>A​(p.Lys62Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 1,613,828 control chromosomes in the GnomAD database, including 78,287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6523 hom., cov: 32)
  • Exomes 𝑓: 0.31 (71764 hom.)
• Consequence: PALLD NM_001166108.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.92

Genes affected

PALLD (HGNC:17068): (palladin, cytoskeletal associated protein) This gene encodes a cytoskeletal protein that is required for organizing the actin cytoskeleton. The protein is a component of actin-containing microfilaments, and it is involved in the control of cell shape, adhesion, and contraction. Polymorphisms in this gene are associated with a susceptibility to pancreatic cancer type 1, and also with a risk for myocardial infarction. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

DDX60L (HGNC:26429): (DExD/H-box 60 like) This gene encodes a member of the DExD/H-box helicase family of proteins, a subset of the super family 2 helicases. Members of the DExD/H-box helicase family share a conserved functional core comprised of two RecA-like globular domains. These domains contain conserved motifs that mediate ATP binding, ATP hydrolysis, nucleic acid binding, and RNA unwinding. In addition to functions in RNA metabolism, members of this family are involved in anti-viral immunity and act as cytosolic sensors of viral nucleic acids. The protein encoded by this gene has been shown to inhibit hepatitis C virus replication in response to interferon stimulation in cell culture. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

LOC107986198 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 4-168511690-G-A is Benign according to our data. Variant chr4-168511690-G-A is described in ClinVar as [Benign]. Clinvar id is 348027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.91 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALLD	NM_001166108.2	c.186G>A	p.Lys62Lys	synonymous_variant	Exon 2 of 22	ENST00000505667.6	NP_001159580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALLD	ENST00000505667.6	c.186G>A	p.Lys62Lys	synonymous_variant	Exon 2 of 22	1	NM_001166108.2	ENSP00000425556.1

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44050 AN: 152022 Hom.: 6522 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.279

GnomAD3 exomes AF: 0.280 AC: 70202 AN: 250894 Hom.: 10575 AF XY: 0.282 AC XY: 38226 AN XY: 135598

Gnomad AFR exome AF: 0.230

Gnomad AMR exome AF: 0.180

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.175

Gnomad SAS exome AF: 0.225

Gnomad FIN exome AF: 0.399

Gnomad NFE exome AF: 0.324

Gnomad OTH exome AF: 0.294

GnomAD4 exome AF: 0.309 AC: 452104 AN: 1461688 Hom.: 71764 Cov.: 38 AF XY: 0.307 AC XY: 223535 AN XY: 727142

Gnomad4 AFR exome AF: 0.226

Gnomad4 AMR exome AF: 0.188

Gnomad4 ASJ exome AF: 0.298

Gnomad4 EAS exome AF: 0.193

Gnomad4 SAS exome AF: 0.228

Gnomad4 FIN exome AF: 0.393

Gnomad4 NFE exome AF: 0.325

Gnomad4 OTH exome AF: 0.295

GnomAD4 genome AF: 0.290 AC: 44059 AN: 152140 Hom.: 6523 Cov.: 32 AF XY: 0.289 AC XY: 21488 AN XY: 74372

Gnomad4 AFR AF: 0.233

Gnomad4 AMR AF: 0.240

Gnomad4 ASJ AF: 0.281

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.396

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.275

Alfa AF: 0.307 Hom.: 4870

Bravo AF: 0.275

Asia WGS AF: 0.195 AC: 679 AN: 3478

EpiCase AF: 0.319

EpiControl AF: 0.315

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Jul 30, 2020

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Pancreatic cancer, susceptibility to, 1 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pancreatic adenocarcinoma Benign:1

Nov 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.0
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs1806729; hg19: chr4-169432841; COSMIC: COSV54981231; COSMIC: COSV54981231;