6-34530351-G-C

Position:

• chr6-34530351-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020804.5(PACSIN1):​c.897G>C​(p.Trp299Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PACSIN1 NM_020804.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PACSIN1	NM_020804.5	c.897G>C	p.Trp299Cys	missense_variant	7/10	ENST00000244458.7	NP_065855.1
PACSIN1	NM_001199583.3	c.897G>C	p.Trp299Cys	missense_variant	7/10		NP_001186512.1
PACSIN1	XM_011514541.2	c.897G>C	p.Trp299Cys	missense_variant	7/10		XP_011512843.1
PACSIN1	XM_047418689.1	c.897G>C	p.Trp299Cys	missense_variant	7/10		XP_047274645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PACSIN1	ENST00000244458.7	c.897G>C	p.Trp299Cys	missense_variant	7/10	1	NM_020804.5	ENSP00000244458.2
PACSIN1	ENST00000538621.2	c.897G>C	p.Trp299Cys	missense_variant	7/10	1		ENSP00000439639.1
PACSIN1	ENST00000620693.4	c.897G>C	p.Trp299Cys	missense_variant	7/10	1		ENSP00000484060.1
PACSIN1	ENST00000374043.6	c.771G>C	p.Trp257Cys	missense_variant	7/10	1		ENSP00000363155.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461708 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727150

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 04, 2024

The c.897G>C (p.W299C) alteration is located in exon 7 (coding exon 6) of the PACSIN1 gene. This alteration results from a G to C substitution at nucleotide position 897, causing the tryptophan (W) at amino acid position 299 to be replaced by a cysteine (C). 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	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;T;D;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D;.;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Pathogenic	3.1	M;.;M;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-12	.;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	.;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.89
MutPred		0.38		Gain of disorder (P = 0.1424);.;Gain of disorder (P = 0.1424);Gain of disorder (P = 0.1424);
MVP		0.64
MPC		1.7
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.90
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-34498128;