6-32121077-G-C

Variant names:

• chr6-32121077-G-C
• rs2228628
• NM_004381.5:c.612C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004381.5(ATF6B):​c.612C>G​(p.Ser204Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,567,354 control chromosomes in the GnomAD database, including 59,883 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.23 (5172 hom., cov: 32)
  • Exomes 𝑓: 0.27 (54711 hom.)
• Consequence: ATF6B NM_004381.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.116
• Publications: 40 publications found

Genes affected

ATF6B (HGNC:2349): (activating transcription factor 6 beta) The protein encoded by this gene is a transcription factor in the unfolded protein response (UPR) pathway during ER stress. Either as a homodimer or as a heterodimer with ATF6-alpha, the encoded protein binds to the ER stress response element, interacting with nuclear transcription factor Y to activate UPR target genes. The protein is normally found in the membrane of the endoplasmic reticulum; however, under ER stress, the N-terminal cytoplasmic domain is cleaved from the rest of the protein and translocates to the nucleus. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP7: Synonymous conserved (PhyloP=-0.116 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATF6B	NM_004381.5	c.612C>G	p.Ser204Ser	synonymous_variant	Exon 7 of 18	ENST00000375203.8	NP_004372.3
ATF6B	NM_001136153.2	c.603C>G	p.Ser201Ser	synonymous_variant	Exon 7 of 18		NP_001129625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATF6B	ENST00000375203.8	c.612C>G	p.Ser204Ser	synonymous_variant	Exon 7 of 18	1	NM_004381.5	ENSP00000364349.3

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34959 AN: 152000 Hom.: 5168 Cov.: 32

Gnomad AFR AF: 0.0561

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.244

GnomAD2 exomes AF: 0.266 AC: 55532 AN: 209080 AF XY: 0.269

Gnomad AFR exome AF: 0.0494

Gnomad AMR exome AF: 0.292

Gnomad ASJ exome AF: 0.432

Gnomad EAS exome AF: 0.152

Gnomad FIN exome AF: 0.373

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.270 AC: 382429 AN: 1415236 Hom.: 54711 Cov.: 34 AF XY: 0.271 AC XY: 189428 AN XY: 699822

African (AFR) AF: 0.0470 AC: 1505 AN: 32024

American (AMR) AF: 0.290 AC: 11123 AN: 38362

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 9728 AN: 22142

East Asian (EAS) AF: 0.199 AC: 7854 AN: 39472

South Asian (SAS) AF: 0.195 AC: 15209 AN: 78056

European-Finnish (FIN) AF: 0.367 AC: 18753 AN: 51094

Middle Eastern (MID) AF: 0.318 AC: 1743 AN: 5478

European-Non Finnish (NFE) AF: 0.276 AC: 301293 AN: 1090306

Other (OTH) AF: 0.261 AC: 15221 AN: 58302

GnomAD4 genome AF: 0.230 AC: 34971 AN: 152118 Hom.: 5172 Cov.: 32 AF XY: 0.235 AC XY: 17442 AN XY: 74364

African (AFR) AF: 0.0560 AC: 2325 AN: 41522

American (AMR) AF: 0.297 AC: 4538 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1591 AN: 3468

East Asian (EAS) AF: 0.162 AC: 839 AN: 5172

South Asian (SAS) AF: 0.190 AC: 916 AN: 4818

European-Finnish (FIN) AF: 0.387 AC: 4092 AN: 10584

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.290 AC: 19736 AN: 67968

Other (OTH) AF: 0.245 AC: 519 AN: 2116

Alfa AF: 0.279 Hom.: 4222

Bravo AF: 0.218

Asia WGS AF: 0.202 AC: 704 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.0
DANN	Benign	0.35
PhyloP100		-0.12
Mutation Taster		=98/2	polymorphism (auto)

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: rs2228628; hg19: chr6-32088854; COSMIC: COSV64352627; COSMIC: COSV64352627;