7-6466238-G-T
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_006854.4(KDELR2):c.437C>A(p.Thr146Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000046 ( 0 hom. )
Consequence
KDELR2
NM_006854.4 missense
NM_006854.4 missense
Scores
3
5
11
Clinical Significance
Conservation
PhyloP100: 9.89
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000458 (67/1461862) while in subpopulation NFE AF= 0.0000459 (51/1111982). AF 95% confidence interval is 0.0000355. There are 0 homozygotes in gnomad4_exome. There are 36 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KDELR2 | NM_006854.4 | c.437C>A | p.Thr146Asn | missense_variant | 4/5 | ENST00000258739.9 | NP_006845.1 | |
KDELR2 | NM_001100603.2 | c.352-3063C>A | intron_variant | NP_001094073.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KDELR2 | ENST00000258739.9 | c.437C>A | p.Thr146Asn | missense_variant | 4/5 | 1 | NM_006854.4 | ENSP00000258739 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152120Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000139 AC: 35AN: 251490Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135922
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GnomAD4 exome AF: 0.0000458 AC: 67AN: 1461862Hom.: 0 Cov.: 29 AF XY: 0.0000495 AC XY: 36AN XY: 727232
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152120Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74306
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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 submitter | clinical testing | Ambry Genetics | Nov 08, 2021 | The c.437C>A (p.T146N) alteration is located in exon 4 (coding exon 4) of the KDELR2 gene. This alteration results from a C to A substitution at nucleotide position 437, causing the threonine (T) at amino acid position 146 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at