rs13222

Positions:

• chr10-4995770-A-C
• chr10-4995770-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001393392.1(AKR1C2):​c.666T>G​(p.His222Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. H222H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 27)
• Consequence: AKR1C2 NM_001393392.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -4.51

Genes affected

AKR1C2 (HGNC:385): (aldo-keto reductase family 1 member C2) This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols using NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme binds bile acid with high affinity, and shows minimal 3-alpha-hydroxysteroid dehydrogenase activity. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-4995770-A-C is Pathogenic according to our data. Variant chr10-4995770-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 30067.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03474471). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1C2	NM_001393392.1	c.666T>G	p.His222Gln	missense_variant	6/9	ENST00000380753.9
LOC101928051	XR_001747340.2			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1C2	ENST00000380753.9	c.666T>G	p.His222Gln	missense_variant	6/9	1	NM_001393392.1	P1
AKR1C2	ENST00000421196.7	c.588T>G	p.His196Gln	missense_variant	5/8	1
	ENST00000451575.6	n.180+103A>C		intron_variant, non_coding_transcript_variant		3
AKR1C2	ENST00000460124.5	n.2126T>G		non_coding_transcript_exon_variant	5/8	5

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 27

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

46,XY disorder of sex development due to testicular 17,20-desmolase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 12, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.0010
DANN	Benign	0.50
DEOGEN2	Benign	0.024	T;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0078	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.035	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.60	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.7	N;N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.0	B;B
Vest4		0.17
MutPred		0.65		Loss of glycosylation at S217 (P = 0.1616);.;
MVP		0.10
MPC		1.7
ClinPred		0.083	T
GERP RS		-5.0
Varity_R		0.63
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs13222; hg19: chr10-5037962;