chr10-5000649-A-T

Variant names:

• chr10-5000649-A-T
• rs797044460
• NM_001393392.1:c.270T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS1 PM2

The NM_001393392.1(AKR1C2):​c.270T>A​(p.His90Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,466 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AKR1C2 NM_001393392.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0220
• Publications: 0 publications found

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]

AKR1C2 Gene-Disease associations (from GenCC):

• 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS1: Transcript NM_001393392.1 (AKR1C2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393392.1. 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
	AKR1C2	NM_001393392.1	MANE Select	c.270T>A	p.His90Gln	missense	Exon 3 of 9	NP_001380321.1	P52895-1
	AKR1C2	NM_001354.6		c.270T>A	p.His90Gln	missense	Exon 5 of 11	NP_001345.1	P52895-1
	AKR1C2	NM_205845.3		c.270T>A	p.His90Gln	missense	Exon 4 of 10	NP_995317.1	P52895-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1C2	ENST00000380753.9	TSL:1 MANE Select	c.270T>A	p.His90Gln	missense	Exon 3 of 9	ENSP00000370129.4	P52895-1
	AKR1C2	ENST00000421196.7	TSL:1	c.270T>A	p.His90Gln	missense	Exon 3 of 8	ENSP00000392694.2	B4DK69
	AKR1C2	ENST00000867375.1		c.393T>A	p.His131Gln	missense	Exon 4 of 10	ENSP00000537434.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461466 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727024

⚠️ 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: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111784

Other (OTH) AF: 0.00 AC: 0 AN: 60370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0039	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.85	L
PhyloP100		-0.022
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.25
Sift	Benign	0.095	T
Sift4G	Uncertain	0.012	D
Polyphen		0.16	B
Vest4		0.20
MutPred		0.69		Gain of solvent accessibility (P = 0.0338)
MVP		0.54
MPC		0.56
ClinPred		0.88	D
GERP RS		0.49
Varity_R		0.46
gMVP		0.51
Mutation Taster		=3/97	disease causing

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: rs797044460; hg19: chr10-5042841;