chr6-34528674-G-A

Position:

• chr6-34528674-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_020804.5(PACSIN1):​c.253G>A​(p.Gly85Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PACSIN1 NM_020804.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18

Genes affected

PACSIN1 (HGNC:8570): (protein kinase C and casein kinase substrate in neurons 1) Enables phospholipid binding activity. Involved in plasma membrane tubulation. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PACSIN1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19256645).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PACSIN1	NM_020804.5	c.253G>A	p.Gly85Ser	missense_variant	4/10	ENST00000244458.7	NP_065855.1
PACSIN1	NM_001199583.3	c.253G>A	p.Gly85Ser	missense_variant	4/10		NP_001186512.1
PACSIN1	XM_011514541.2	c.253G>A	p.Gly85Ser	missense_variant	4/10		XP_011512843.1
PACSIN1	XM_047418689.1	c.253G>A	p.Gly85Ser	missense_variant	4/10		XP_047274645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PACSIN1	ENST00000244458.7	c.253G>A	p.Gly85Ser	missense_variant	4/10	1	NM_020804.5	ENSP00000244458.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461744 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2024

The c.253G>A (p.G85S) alteration is located in exon 4 (coding exon 3) of the PACSIN1 gene. This alteration results from a G to A substitution at nucleotide position 253, causing the glycine (G) at amino acid position 85 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Benign	0.88
DEOGEN2	Benign	0.055	T;T;T;T
Eigen	Benign	0.035
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	.;D;.;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;.;L;L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	1.1	.;N;N;N
REVEL	Benign	0.053
Sift	Benign	0.46	.;T;T;T
Sift4G	Benign	0.43	T;T;T;T
Polyphen		0.67	P;.;P;P
Vest4		0.28
MutPred		0.50		Gain of phosphorylation at G85 (P = 0.0635);.;Gain of phosphorylation at G85 (P = 0.0635);Gain of phosphorylation at G85 (P = 0.0635);
MVP		0.44
MPC		0.69
ClinPred		0.28	T
GERP RS		4.0
Varity_R		0.15
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1767532143; hg19: chr6-34496451;