2-232456669-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001631.5(ALPI):​c.274C>T​(p.Arg92Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,609,262 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0055 ( 6 hom., cov: 32)
Exomes 𝑓: 0.00061 ( 6 hom. )

Consequence

ALPI
NM_001631.5 missense

Scores

2
7
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: -2.27
Variant links:
Genes affected
ALPI (HGNC:437): (alkaline phosphatase, intestinal) There are at least four distinct but related alkaline phosphatases: intestinal, placental, placental-like, and liver/bone/kidney (tissue non-specific). The intestinal alkaline phosphatase gene encodes a digestive brush-border enzyme. This enzyme is a component of the gut mucosal defense system and is thought to function in the detoxification of lipopolysaccharide, and in the prevention of bacterial translocation in the gut. [provided by RefSeq, Dec 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.016060501).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00554 (842/152088) while in subpopulation AFR AF= 0.0195 (809/41492). AF 95% confidence interval is 0.0184. There are 6 homozygotes in gnomad4. There are 371 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALPINM_001631.5 linkc.274C>T p.Arg92Cys missense_variant Exon 3 of 11 ENST00000295463.4 NP_001622.2 P09923A0A024R4A2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALPIENST00000295463.4 linkc.274C>T p.Arg92Cys missense_variant Exon 3 of 11 1 NM_001631.5 ENSP00000295463.3 P09923
ALPIENST00000457560.1 linkn.*203C>T non_coding_transcript_exon_variant Exon 2 of 10 5 ENSP00000413068.1 F8WEQ0
ALPIENST00000457560.1 linkn.*203C>T 3_prime_UTR_variant Exon 2 of 10 5 ENSP00000413068.1 F8WEQ0

Frequencies

GnomAD3 genomes
AF:
0.00553
AC:
841
AN:
151970
Hom.:
6
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0195
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00105
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00479
GnomAD3 exomes
AF:
0.00141
AC:
338
AN:
240484
Hom.:
0
AF XY:
0.00110
AC XY:
143
AN XY:
130156
show subpopulations
Gnomad AFR exome
AF:
0.0192
Gnomad AMR exome
AF:
0.000747
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000564
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000167
Gnomad OTH exome
AF:
0.000337
GnomAD4 exome
AF:
0.000608
AC:
886
AN:
1457174
Hom.:
6
Cov.:
33
AF XY:
0.000534
AC XY:
387
AN XY:
724526
show subpopulations
Gnomad4 AFR exome
AF:
0.0194
Gnomad4 AMR exome
AF:
0.000818
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.0000234
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000118
Gnomad4 OTH exome
AF:
0.00106
GnomAD4 genome
AF:
0.00554
AC:
842
AN:
152088
Hom.:
6
Cov.:
32
AF XY:
0.00499
AC XY:
371
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.0195
Gnomad4 AMR
AF:
0.00105
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000883
Gnomad4 OTH
AF:
0.00474
Alfa
AF:
0.00138
Hom.:
13
Bravo
AF:
0.00694
ESP6500AA
AF:
0.0193
AC:
85
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00182
AC:
221
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Aug 16, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BS1 -

ALPI-related disorder Benign:1
Oct 28, 2019
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as 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
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.91
D
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.81
FATHMM_MKL
Benign
0.10
N
LIST_S2
Uncertain
0.93
D
MetaRNN
Benign
0.016
T
MetaSVM
Uncertain
0.43
D
MutationAssessor
Pathogenic
3.3
M
PrimateAI
Benign
0.18
T
PROVEAN
Uncertain
-2.9
D
REVEL
Uncertain
0.38
Sift
Uncertain
0.0080
D
Sift4G
Uncertain
0.017
D
Polyphen
0.96
D
Vest4
0.32
MVP
0.73
MPC
0.67
ClinPred
0.11
T
GERP RS
-4.6
Varity_R
0.22
gMVP
0.73

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: rs61732024; hg19: chr2-233321379; API