7-6463130-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The ENST00000490996.1(KDELR2):​c.397C>T​(p.Pro133Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,614,126 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000096 ( 1 hom. )

Consequence

KDELR2
ENST00000490996.1 missense

Scores

5
10

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.269
Variant links:
Genes affected
KDELR2 (HGNC:6305): (KDEL endoplasmic reticulum protein retention receptor 2) Retention of resident soluble proteins in the lumen of the endoplasmic reticulum (ER) is achieved in both yeast and animal cells by their continual retrieval from the cis-Golgi, or a pre-Golgi compartment. Sorting of these proteins is dependent on a C-terminal tetrapeptide signal, usually lys-asp-glu-leu (KDEL) in animal cells, and his-asp-glu-leu (HDEL) in S. cerevisiae. This process is mediated by a receptor that recognizes, and binds the tetrapeptide-containing protein, and returns it to the ER. In yeast, the sorting receptor encoded by a single gene, ERD2, is a seven-transmembrane protein. Unlike yeast, several human homologs of the ERD2 gene, constituting the KDEL receptor gene family, have been described. KDELR2 was the second member of the family to be identified, and it encodes a protein which is 83% identical to the KDELR1 gene product. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]
DAGLB (HGNC:28923): (diacylglycerol lipase beta) Enables lipase activity. Involved in arachidonic acid metabolic process. Located in nucleoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.011856347).
BP6
Variant 7-6463130-G-A is Benign according to our data. Variant chr7-6463130-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3039978.Status of the report is no_assertion_criteria_provided, 0 stars.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000151 (23/152278) while in subpopulation AMR AF= 0.00131 (20/15292). AF 95% confidence interval is 0.000866. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KDELR2NM_006854.4 linkuse as main transcriptc.*11C>T 3_prime_UTR_variant 5/5 ENST00000258739.9 NP_006845.1
KDELR2NM_001100603.2 linkuse as main transcriptc.397C>T p.Pro133Ser missense_variant 4/4 NP_001094073.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KDELR2ENST00000258739.9 linkuse as main transcriptc.*11C>T 3_prime_UTR_variant 5/51 NM_006854.4 ENSP00000258739 P1P33947-1

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152160
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00118
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:
0.000478
GnomAD3 exomes
AF:
0.000398
AC:
100
AN:
251256
Hom.:
0
AF XY:
0.000324
AC XY:
44
AN XY:
135840
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00281
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.0000958
AC:
140
AN:
1461848
Hom.:
1
Cov.:
31
AF XY:
0.0000963
AC XY:
70
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00293
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152278
Hom.:
0
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000204
Hom.:
0
Bravo
AF:
0.000348
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000255
AC:
31

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

KDELR2-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesNov 08, 2023This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
12
DANN
Benign
0.96
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.15
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.38
T
M_CAP
Benign
0.0065
T
MetaRNN
Benign
0.012
T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
D;D;N
PROVEAN
Uncertain
-3.9
D
REVEL
Uncertain
0.38
Sift
Uncertain
0.0070
D
Sift4G
Uncertain
0.0070
D
Polyphen
0.42
B
Vest4
0.41
MVP
0.44
ClinPred
0.12
T
GERP RS
3.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201979585; hg19: chr7-6502761; COSMIC: COSV51727708; API