6-34530547-G-A

Position:

• chr6-34530547-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020804.5(PACSIN1):​c.997G>A​(p.Gly333Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,524 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PACSIN1 NM_020804.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.075627625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PACSIN1	NM_020804.5	c.997G>A	p.Gly333Arg	missense_variant	8/10	ENST00000244458.7	NP_065855.1
PACSIN1	NM_001199583.3	c.997G>A	p.Gly333Arg	missense_variant	8/10		NP_001186512.1
PACSIN1	XM_011514541.2	c.997G>A	p.Gly333Arg	missense_variant	8/10		XP_011512843.1
PACSIN1	XM_047418689.1	c.997G>A	p.Gly333Arg	missense_variant	8/10		XP_047274645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PACSIN1	ENST00000244458.7	c.997G>A	p.Gly333Arg	missense_variant	8/10	1	NM_020804.5	ENSP00000244458.2
PACSIN1	ENST00000538621.2	c.997G>A	p.Gly333Arg	missense_variant	8/10	1		ENSP00000439639.1
PACSIN1	ENST00000620693.4	c.997G>A	p.Gly333Arg	missense_variant	8/10	1		ENSP00000484060.1
PACSIN1	ENST00000374043.6	c.871G>A	p.Gly291Arg	missense_variant	8/10	1		ENSP00000363155.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453524 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722966

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: 9.02e-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

Aug 16, 2021

The c.997G>A (p.G333R) alteration is located in exon 8 (coding exon 7) of the PACSIN1 gene. This alteration results from a G to A substitution at nucleotide position 997, causing the glycine (G) at amino acid position 333 to be replaced by an arginine (R). 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	0.19
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.18	T;T;T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.80	.;T;.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.076	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;L;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.0	.;N;N;N
REVEL	Benign	0.037
Sift	Benign	0.33	.;T;T;T
Sift4G	Benign	0.48	T;T;T;T
Polyphen		0.089	B;.;B;B
Vest4		0.16
MutPred		0.25		Gain of MoRF binding (P = 0.0109);.;Gain of MoRF binding (P = 0.0109);Gain of MoRF binding (P = 0.0109);
MVP		0.36
MPC		0.67
ClinPred		0.30	T
GERP RS		4.6
Varity_R		0.10
gMVP		0.27

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: chr6-34498324;