chr20-18543019-T-C

Variant names:

• chr20-18543019-T-C
• rs138198461
• NM_006363.6:c.1512T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_006363.6(SEC23B):​c.1512T>C​(p.Asn504Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,614,136 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (9 hom.)
• Consequence: SEC23B NM_006363.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001931
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.201
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 20-18543019-T-C is Benign according to our data. Variant chr20-18543019-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 337797.
• BP7: Synonymous conserved (PhyloP=0.201 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00255 (389/152258) while in subpopulation NFE AF = 0.00373 (254/68006). AF 95% confidence interval is 0.00336. There are 1 homozygotes in GnomAd4. There are 186 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC23B	NM_006363.6	MANE Select	c.1512T>C	p.Asn504Asn	splice_region synonymous	Exon 14 of 20	NP_006354.2
	SEC23B	NM_001172745.3		c.1512T>C	p.Asn504Asn	splice_region synonymous	Exon 14 of 20	NP_001166216.1	Q15437
	SEC23B	NM_032985.6		c.1512T>C	p.Asn504Asn	splice_region synonymous	Exon 14 of 20	NP_116780.1	Q15437

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC23B	ENST00000650089.1	MANE Select	c.1512T>C	p.Asn504Asn	splice_region synonymous	Exon 14 of 20	ENSP00000497473.1	Q15437
	SEC23B	ENST00000336714.8	TSL:1	c.1512T>C	p.Asn504Asn	splice_region synonymous	Exon 14 of 20	ENSP00000338844.3	Q15437
	SEC23B	ENST00000377465.6	TSL:1	c.1512T>C	p.Asn504Asn	splice_region synonymous	Exon 14 of 20	ENSP00000366685.1	Q15437

Frequencies

GnomAD3 genomes AF: 0.00256 AC: 389 AN: 152140 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00373

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00299 AC: 752 AN: 251464 AF XY: 0.00307

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00314

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00311 AC: 4542 AN: 1461878 Hom.: 9 Cov.: 32 AF XY: 0.00310 AC XY: 2256 AN XY: 727240

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.00163 AC: 73 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 297 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86258

European-Finnish (FIN) AF: 0.00320 AC: 171 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00338 AC: 3758 AN: 1112000

Other (OTH) AF: 0.00308 AC: 186 AN: 60396

GnomAD4 genome AF: 0.00255 AC: 389 AN: 152258 Hom.: 1 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74442

African (AFR) AF: 0.000409 AC: 17 AN: 41556

American (AMR) AF: 0.00255 AC: 39 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00311 AC: 33 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00373 AC: 254 AN: 68006

Other (OTH) AF: 0.00380 AC: 8 AN: 2106

Alfa AF: 0.00406 Hom.: 4

Bravo AF: 0.00257

EpiCase AF: 0.00300

EpiControl AF: 0.00314

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Congenital dyserythropoietic anemia, type II (2)
-	-	1	Congenital dyserythropoietic anemia, type II;C4225179:Cowden syndrome 7 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.4
DANN	Benign	0.77
PhyloP100		0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.028
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs138198461; hg19: chr20-18523663;