7-6469742-C-T

Variant summary

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

The NM_006854.4(KDELR2):​c.205G>A​(p.Ala69Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

KDELR2
NM_006854.4 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.82
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KDELR2NM_006854.4 linkuse as main transcriptc.205G>A p.Ala69Thr missense_variant 3/5 ENST00000258739.9 NP_006845.1
KDELR2NM_001100603.2 linkuse as main transcriptc.205G>A p.Ala69Thr missense_variant 3/4 NP_001094073.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KDELR2ENST00000258739.9 linkuse as main transcriptc.205G>A p.Ala69Thr missense_variant 3/51 NM_006854.4 ENSP00000258739 P1P33947-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
249848
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135118
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000293
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:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1460342
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
726554
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000451
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 29, 2023The c.205G>A (p.A69T) alteration is located in exon 3 (coding exon 3) of the KDELR2 gene. This alteration results from a G to A substitution at nucleotide position 205, causing the alanine (A) at amino acid position 69 to be replaced by a threonine (T). 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
0.092
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.35
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.082
T;.
Eigen
Benign
0.17
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Benign
0.0075
T
MetaRNN
Uncertain
0.51
D;D
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.2
L;L
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-1.7
N;N
REVEL
Benign
0.12
Sift
Benign
0.40
T;T
Sift4G
Benign
0.48
T;T
Polyphen
0.0010
B;B
Vest4
0.66
MutPred
0.35
Gain of methylation at K64 (P = 0.0738);Gain of methylation at K64 (P = 0.0738);
MVP
0.41
MPC
0.29
ClinPred
0.43
T
GERP RS
5.6
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
3.8
Varity_R
0.18
gMVP
0.75

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: rs1328710222; hg19: chr7-6509373; API