1-19308211-C-T

Variant names:

• chr1-19308211-C-T
• rs859210
• NM_003689.4:c.538G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003689.4(AKR7A2):​c.538G>A​(p.Glu180Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,614,086 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (41 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: AKR7A2 NM_003689.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.26
• Publications: 4 publications found

Genes affected

AKR7A2 (HGNC:389): (aldo-keto reductase family 7 member A2) The protein encoded by this gene belongs to the aldo/keto reductase (AKR) superfamily and AKR7 family, which are involved in the detoxification of aldehydes and ketones. The AKR7 family consists of 3 genes that are present in a cluster on the p arm of chromosome 1. This protein, thought to be localized in the golgi, catalyzes the NADPH-dependent reduction of succinic semialdehyde to the endogenous neuromodulator, gamma-hydroxybutyrate. It may also function as a detoxication enzyme in the reduction of aflatoxin B1 and 2-carboxybenzaldehyde. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008173585).
• BP6: Variant 1-19308211-C-T is Benign according to our data. Variant chr1-19308211-C-T is described in ClinVar as Benign. ClinVar VariationId is 788501.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 = 0.0117 (1785/152260) while in subpopulation AFR AF = 0.0415 (1725/41540). AF 95% confidence interval is 0.0399. There are 41 homozygotes in GnomAd4. There are 783 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003689.4. 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
	AKR7A2	NM_003689.4	MANE Select	c.538G>A	p.Glu180Lys	missense	Exon 3 of 7	NP_003680.2
	AKR7A2	NM_001320979.1		c.486+244G>A		intron	N/A	NP_001307908.1	B4DZX4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR7A2	ENST00000235835.8	TSL:1 MANE Select	c.538G>A	p.Glu180Lys	missense	Exon 3 of 7	ENSP00000235835.3	O43488
	AKR7A2	ENST00000489286.5	TSL:5	c.319G>A	p.Glu107Lys	missense	Exon 3 of 5	ENSP00000419936.1	H7C5H7
	AKR7A2	ENST00000330072.10	TSL:2	c.486+244G>A		intron	N/A	ENSP00000339084.5	H3BLU7

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1781 AN: 152142 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.0416

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

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: 0.000176

Gnomad OTH AF: 0.00862

GnomAD2 exomes AF: 0.00305 AC: 766 AN: 251462 AF XY: 0.00205

Gnomad AFR exome AF: 0.0423

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00111 AC: 1626 AN: 1461826 Hom.: 23 Cov.: 31 AF XY: 0.000942 AC XY: 685 AN XY: 727206

African (AFR) AF: 0.0398 AC: 1333 AN: 33472

American (AMR) AF: 0.00208 AC: 93 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111972

Other (OTH) AF: 0.00235 AC: 142 AN: 60386

GnomAD4 genome AF: 0.0117 AC: 1785 AN: 152260 Hom.: 41 Cov.: 33 AF XY: 0.0105 AC XY: 783 AN XY: 74442

African (AFR) AF: 0.0415 AC: 1725 AN: 41540

American (AMR) AF: 0.00196 AC: 30 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68014

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.00505 Hom.: 15

Bravo AF: 0.0136

ESP6500AA AF: 0.0404 AC: 178

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00382 AC: 464

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.77	N
PhyloP100		7.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.19
Sift	Benign	0.095	T
Sift4G	Benign	0.18	T
Polyphen		0.50	P
Vest4		0.78
MVP		0.43
MPC		0.14
ClinPred		0.10	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.58
gMVP		0.31
Mutation Taster		=90/10	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: rs859210; hg19: chr1-19634705; COSMIC: COSV107245481; COSMIC: COSV107245481;