Genetic Variant SNX21:p.His2Asp (chr20-45833923-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033421.4(SNX21):c.4C>G(p.His2Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SNX21
NM_033421.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.76

Variant links:

Genes affected

SNX21 (HGNC:16154): (sorting nexin family member 21) This gene encodes a member of the sorting nexin family. Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. This protein does not contain a coiled coil region, like some family members. The specific function of this protein has not been determined. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

SNX21 links:

TNNC2 (HGNC:11944): (troponin C2, fast skeletal type) Troponin (Tn), a key protein complex in the regulation of striated muscle contraction, is composed of 3 subunits. The Tn-I subunit inhibits actomyosin ATPase, the Tn-T subunit binds tropomyosin and Tn-C, while the Tn-C subunit binds calcium and overcomes the inhibitory action of the troponin complex on actin filaments. The protein encoded by this gene is the Tn-C subunit. [provided by RefSeq, Jul 2008]

TNNC2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14240718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNX21	NM_033421.4 link	c.4C>G	p.His2Asp	missense_variant	Exon 1 of 4	ENST00000491381.6	NP_219489.1	Q969T3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNX21	ENST00000491381.6 link	c.4C>G	p.His2Asp	missense_variant	Exon 1 of 4	1	NM_033421.4	ENSP00000418593.1		Q969T3-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1274426

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

624146

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

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:

0.00

ExAC

AF:

0.0000137

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4C>G (p.H2D) alteration is located in exon 1 (coding exon 1) of the SNX21 gene. This alteration results from a C to G substitution at nucleotide position 4, causing the histidine (H) at amino acid position 2 to be replaced by an aspartic acid (D). 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

0.13

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.0079

T;.;T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.44

T;T;T;T

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N;N;N

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.58

.;N;N;N

REVEL

Benign

0.075

Sift

Pathogenic

0.0

.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.065

B;.;B;.

Vest4

0.42

MutPred

0.20

Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);

MVP

0.15

MPC

0.46

ClinPred

0.29

GERP RS

3.5

Varity_R

0.24

gMVP

0.20

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over