chr1-2508954-G-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_018216.4(PANK4):​c.2215C>T​(p.Arg739Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,609,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R739H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PANK4
NM_018216.4 missense

Scores

2
13

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.02

Publications

0 publications found
Variant links:
Genes affected
PANK4 (HGNC:19366): (pantothenate kinase 4 (inactive)) This gene encodes a protein belonging to the pantothenate kinase family. Pantothenate kinase is a key regulatory enzyme in the biosynthesis of coenzyme A (CoA) in bacteria and mammalian cells. It catalyzes the first committed step in the universal biosynthetic pathway leading to CoA and is itself subject to regulation through feedback inhibition by CoA. This family member is most abundant in muscle but is expressed in all tissues. [provided by RefSeq, Jul 2008]
PANK4 Gene-Disease associations (from GenCC):
  • early-onset posterior polar cataract
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • cataract
    Inheritance: AD Classification: LIMITED Submitted by: G2P
  • cataract 49
    Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.071370184).
BP6
Variant 1-2508954-G-A is Benign according to our data. Variant chr1-2508954-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3927693.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAdExome4 at 6 AD,Unknown gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PANK4NM_018216.4 linkc.2215C>T p.Arg739Cys missense_variant Exon 19 of 19 ENST00000378466.9 NP_060686.3 Q9NVE7
PANK4XM_047424306.1 linkc.1774C>T p.Arg592Cys missense_variant Exon 19 of 19 XP_047280262.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PANK4ENST00000378466.9 linkc.2215C>T p.Arg739Cys missense_variant Exon 19 of 19 1 NM_018216.4 ENSP00000367727.5 Q9NVE7
PANK4ENST00000435556.8 linkc.2098C>T p.Arg700Cys missense_variant Exon 19 of 19 2 ENSP00000421433.3 E9PHT6
PANK4ENST00000505228.5 linkn.*333C>T non_coding_transcript_exon_variant Exon 16 of 16 5 ENSP00000425932.1 H0YA26
PANK4ENST00000505228.5 linkn.*333C>T 3_prime_UTR_variant Exon 16 of 16 5 ENSP00000425932.1 H0YA26

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152014
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000967
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000822
AC:
2
AN:
243438
AF XY:
0.00000755
show subpopulations
Gnomad AFR exome
AF:
0.0000652
Gnomad AMR exome
AF:
0.0000294
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000412
AC:
6
AN:
1457152
Hom.:
0
Cov.:
31
AF XY:
0.00000552
AC XY:
4
AN XY:
724842
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33436
American (AMR)
AF:
0.0000225
AC:
1
AN:
44452
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26036
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39640
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85770
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51494
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5738
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1110336
Other (OTH)
AF:
0.00
AC:
0
AN:
60250
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.400
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152014
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74238
show subpopulations
African (AFR)
AF:
0.0000967
AC:
4
AN:
41384
American (AMR)
AF:
0.00
AC:
0
AN:
15260
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5148
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4816
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10600
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68018
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000166
AC:
2

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Apr 04, 2025
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.091
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.67
CADD
Benign
20
DANN
Benign
0.94
Eigen
Benign
-0.80
Eigen_PC
Benign
-0.67
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Uncertain
0.87
D;.
M_CAP
Benign
0.061
D
MetaRNN
Benign
0.071
T;T
MetaSVM
Benign
-1.0
T
PhyloP100
1.0
PrimateAI
Benign
0.41
T
REVEL
Benign
0.075
Sift4G
Benign
0.072
T;T
Vest4
0.078
MVP
0.043
MPC
0.84
ClinPred
0.13
T
GERP RS
3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=73/27
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

Publications

Other links and lift over

dbSNP: rs753762604; hg19: chr1-2440393; API