Genetic Variant NM_006363.6:c.1484G>A (chr20-18542375-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006363.6(SEC23B):c.1484G>A(p.Arg495His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,158 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R495C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0062 ( 12 hom., cov: 33)

Exomes 𝑓: 0.00072 ( 22 hom. )

Consequence

SEC23B
NM_006363.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 10.0

Publications

5 publications found

Variant links:

Genes affected

SEC23B (HGNC:10702): (SEC23 homolog B, COPII coat complex component) The protein encoded by this gene is a member of the SEC23 subfamily of the SEC23/SEC24 family, which is involved in vesicle trafficking. The encoded protein has similarity to yeast Sec23p component of COPII. COPII is the coat protein complex responsible for vesicle budding from the ER. The function of this gene product has been implicated in cargo selection and concentration. Multiple alternatively spliced transcript variants have been identified in this gene. [provided by RefSeq, Feb 2010]

SEC23B Gene-Disease associations (from GenCC):

congenital dyserythropoietic anemia type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P, PanelApp Australia, Laboratory for Molecular Medicine
Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cowden syndrome 7
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
congenital dyserythropoietic anemia
Inheritance: AR Classification: LIMITED Submitted by: Genomics England PanelApp

SEC23B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011357635).

BP6

Variant 20-18542375-G-A is Benign according to our data. Variant chr20-18542375-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0062 (945/152308) while in subpopulation AFR AF = 0.0217 (902/41566). AF 95% confidence interval is 0.0205. There are 12 homozygotes in GnomAd4. There are 469 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006363.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SEC23B	NM_006363.6	MANE Select	c.1484G>A	p.Arg495His	missense	Exon 13 of 20	NP_006354.2
SEC23B	NM_001172745.3		c.1484G>A	p.Arg495His	missense	Exon 13 of 20	NP_001166216.1	Q15437
SEC23B	NM_032985.6		c.1484G>A	p.Arg495His	missense	Exon 13 of 20	NP_116780.1	Q15437

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SEC23B	ENST00000650089.1	MANE Select	c.1484G>A	p.Arg495His	missense	Exon 13 of 20	ENSP00000497473.1	Q15437
SEC23B	ENST00000336714.8	TSL:1	c.1484G>A	p.Arg495His	missense	Exon 13 of 20	ENSP00000338844.3	Q15437
SEC23B	ENST00000377465.6	TSL:1	c.1484G>A	p.Arg495His	missense	Exon 13 of 20	ENSP00000366685.1	Q15437

Frequencies

GnomAD3 genomes

AF:

0.00605

AC:

921

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0212

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00181

AC:

455

AN:

251432

AF XY:

0.00130

show subpopulations

Gnomad AFR exome

AF:

0.0226

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000718

AC:

1049

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000678

AC XY:

493

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0239

AC:

799

AN:

33480

American (AMR)

AF:

0.00165

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.000197

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000342

AC:

AN:

1111984

Other (OTH)

AF:

0.00171

AC:

103

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00620

AC:

945

AN:

152308

Hom.:

Cov.:

AF XY:

0.00630

AC XY:

469

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0217

AC:

902

AN:

41566

American (AMR)

AF:

0.00203

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68028

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

102

152

203

254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00222

Hom.:

Bravo

AF:

0.00740

ESP6500AA

AF:

0.0216

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00217

AC:

263

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital dyserythropoietic anemia, type II (1)

Congenital dyserythropoietic anemia, type II;C4225179:Cowden syndrome 7 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.71

MutationAssessor

Uncertain

2.7

PhyloP100

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.67

Sift

Benign

0.12

Sift4G

Uncertain

0.055

Polyphen

0.96

Vest4

0.88

MVP

0.97

MPC

0.27

ClinPred

0.034

GERP RS

4.8

PromoterAI

-0.0064

Neutral

(source)

Varity_R

0.39

gMVP

0.77

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over