NM_001166108.2:c.2199+8G>A

Variant names:

• chr4-168894685-G-A
• rs200060953
• NM_001166108.2:c.2199+8G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001166108.2(PALLD):​c.2199+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0008 in 1,612,400 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (6 hom.)
• Consequence: PALLD NM_001166108.2 splice_region, intron
• Scores: Splicing: ADA: 0.0005558
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0110
• Publications: 0 publications found

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]

CBR4 (HGNC:25891): (carbonyl reductase 4) Enables several functions, including 3-oxoacyl-[acyl-carrier-protein] reductase (NADPH) activity; NADPH binding activity; and NADPH dehydrogenase (quinone) activity. Involved in fatty acid biosynthetic process; glycoside metabolic process; and protein tetramerization. Located in mitochondrial matrix. Part of oxidoreductase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-168894685-G-A is Benign according to our data. Variant chr4-168894685-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 116 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166108.2. 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
	PALLD	NM_001166108.2	MANE Select	c.2199+8G>A		splice_region intron	N/A	NP_001159580.1
	PALLD	NM_016081.4		c.2199+8G>A		splice_region intron	N/A	NP_057165.3
	PALLD	NM_001166109.2		c.1053+8G>A		splice_region intron	N/A	NP_001159581.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALLD	ENST00000505667.6	TSL:1 MANE Select	c.2199+8G>A		splice_region intron	N/A	ENSP00000425556.1
	PALLD	ENST00000261509.10	TSL:1	c.2199+8G>A		splice_region intron	N/A	ENSP00000261509.6
	PALLD	ENST00000507735.6	TSL:1	c.738+8G>A		splice_region intron	N/A	ENSP00000424016.1

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.000800 AC: 199 AN: 248804 AF XY: 0.000870

Gnomad AFR exome AF: 0.000559

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.000804 AC: 1174 AN: 1460068 Hom.: 6 Cov.: 30 AF XY: 0.000869 AC XY: 631 AN XY: 726256

African (AFR) AF: 0.00147 AC: 49 AN: 33410

American (AMR) AF: 0.000940 AC: 42 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.000826 AC: 71 AN: 85966

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53258

Middle Eastern (MID) AF: 0.0175 AC: 101 AN: 5764

European-Non Finnish (NFE) AF: 0.000733 AC: 814 AN: 1110954

Other (OTH) AF: 0.00148 AC: 89 AN: 60314

GnomAD4 genome AF: 0.000761 AC: 116 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74488

African (AFR) AF: 0.000577 AC: 24 AN: 41584

American (AMR) AF: 0.000588 AC: 9 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68024

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.000859 Hom.: 0

Bravo AF: 0.000771

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Pancreatic cancer, susceptibility to, 1 (2)
-	-	1	not provided (1)
-	-	1	Pancreatic adenocarcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.8
DANN	Benign	0.63
PhyloP100		0.011
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00056
dbscSNV1_RF	Benign	0.0
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: rs200060953; hg19: chr4-169815836; COSMIC: COSV105053165;