NM_018252.3:c.750G>C

Variant names:

• chr1-212377595-C-G
• rs775315280
• NM_018252.3:c.750G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018252.3(PACC1):​c.750G>C​(p.Glu250Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: PACC1 NM_018252.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.394
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11052778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PACC1	NM_018252.3	c.750G>C	p.Glu250Asp	missense_variant	Exon 6 of 8	ENST00000261455.9	NP_060722.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PACC1	ENST00000261455.9	c.750G>C	p.Glu250Asp	missense_variant	Exon 6 of 8	1	NM_018252.3	ENSP00000261455.4
PACC1	ENST00000535273.2	c.933G>C	p.Glu311Asp	missense_variant	Exon 7 of 9	2		ENSP00000438863.1
PACC1	ENST00000467822.5	n.656G>C		non_coding_transcript_exon_variant	Exon 5 of 6	3
PACC1	ENST00000478166.5	n.112G>C		non_coding_transcript_exon_variant	Exon 1 of 3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.933G>C (p.E311D) alteration is located in exon 7 (coding exon 7) of the TMEM206 gene. This alteration results from a G to C substitution at nucleotide position 933, causing the glutamic acid (E) at amino acid position 311 to be replaced by an aspartic acid (D). 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	0.27
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.8	L;.
PhyloP100		0.39
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.15
Sift	Uncertain	0.019	D;D
Sift4G	Uncertain	0.045	D;D
Polyphen		0.59	P;.
Vest4		0.25
MutPred		0.24		Loss of methylation at K246 (P = 0.1228);.;
MVP		0.030
MPC		0.68
ClinPred		0.77	D
GERP RS		3.0
Varity_R		0.40
gMVP		0.23
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs775315280; hg19: chr1-212550937; COSMIC: COSV108001198;