1-212375299-G-C

Variant names:

• chr1-212375299-G-C
• rs774466596
• NM_018252.3:c.785C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018252.3(PACC1):​c.785C>G​(p.Thr262Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T262I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PACC1 NM_018252.3 missense, splice_region
• Scores: Splicing: ADA: 0.9716
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.77
• Publications: 0 publications found

Genes affected

PACC1 (HGNC:25593): (proton activated chloride channel 1) Enables pH-gated chloride channel activity. Involved in chloride transport. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PACC1	NM_018252.3	c.785C>G	p.Thr262Arg	missense_variant, splice_region_variant	Exon 7 of 8	ENST00000261455.9	NP_060722.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PACC1	ENST00000261455.9	c.785C>G	p.Thr262Arg	missense_variant, splice_region_variant	Exon 7 of 8	1	NM_018252.3	ENSP00000261455.4
PACC1	ENST00000535273.2	c.968C>G	p.Thr323Arg	missense_variant, splice_region_variant	Exon 8 of 9	2		ENSP00000438863.1
PACC1	ENST00000467822.5	n.691C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 6	3
PACC1	ENST00000478166.5	n.238C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.8	L;.
PhyloP100		6.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;.
Vest4		0.70
MutPred		0.33		Gain of MoRF binding (P = 0.0564);.;
MVP		0.11
MPC		0.86
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.87
gMVP		0.69
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.14		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: rs774466596; hg19: chr1-212548641;