chr1-177932546-C-A

Variant names:

• chr1-177932546-C-A
• rs372353418
• NM_033127.4:c.2956G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033127.4(SEC16B):​c.2956G>T​(p.Ala986Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,409,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A986T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SEC16B NM_033127.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.927
• Publications: 0 publications found

Genes affected

SEC16B (HGNC:30301): (SEC16 homolog B, endoplasmic reticulum export factor) SEC16B is a mammalian homolog of S. cerevisiae Sec16 that is required for organization of transitional endoplasmic reticulum (ER) sites and protein export (Bhattacharyya and Glick, 2007 [PubMed 17192411]).[supplied by OMIM, Jun 2009]

CRYZL2P-SEC16B (HGNC:53757): (CRYZL2P-SEC16B readthrough) This locus represents naturally occurring read-through transcription between the neighboring CRYZL2P (crystallin zeta like 2 pseudogene) and SEC16B (SEC16 homolog B, endoplasmic reticulum export factor) genes on chromosome 1. The readthrough transcript encodes a protein that shares sequence identity with the downstream gene product. [provided by RefSeq, Oct 2017]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031648427).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033127.4. 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
	SEC16B	NM_033127.4	MANE Select	c.2956G>T	p.Ala986Ser	missense	Exon 24 of 26	NP_149118.2	Q96JE7-1
	SEC16B	NM_001390834.1		c.2962G>T	p.Ala988Ser	missense	Exon 24 of 26	NP_001377763.1
	SEC16B	NM_001390835.1		c.2962G>T	p.Ala988Ser	missense	Exon 24 of 26	NP_001377764.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC16B	ENST00000308284.11	TSL:1 MANE Select	c.2956G>T	p.Ala986Ser	missense	Exon 24 of 26	ENSP00000308339.6	Q96JE7-1
	SEC16B	ENST00000528461.5	TSL:1	n.*1943G>T		non_coding_transcript_exon	Exon 23 of 25	ENSP00000475522.1	U3KQ39
	SEC16B	ENST00000528461.5	TSL:1	n.*1943G>T		3_prime_UTR	Exon 23 of 25	ENSP00000475522.1	U3KQ39

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 169952 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1409084 Hom.: 0 Cov.: 33 AF XY: 0.00000144 AC XY: 1 AN XY: 696166

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31634

American (AMR) AF: 0.00 AC: 0 AN: 37726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24954

East Asian (EAS) AF: 0.00 AC: 0 AN: 36052

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085430

Other (OTH) AF: 0.00 AC: 0 AN: 58382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.026
DANN	Benign	0.67
DEOGEN2	Benign	0.0031	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.93
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.0040
Sift	Benign	0.79	T
Sift4G	Benign	0.81	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.37		Gain of phosphorylation at A986 (P = 0.0013)
MVP		0.061
MPC		0.037
ClinPred		0.16	T
GERP RS		-6.2
Varity_R		0.043
gMVP		0.12
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs372353418; hg19: chr1-177901681;