11-83225004-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001300975.2(ANKRD42):c.736C>A(p.Gln246Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,612,920 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: ANKRD42 NM_001300975.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

Genes affected

ANKRD42 (HGNC:26752): (ankyrin repeat domain 42) Predicted to enable NF-kappaB binding activity. Predicted to act upstream of or within positive regulation of NF-kappaB transcription factor activity and positive regulation of cytokine production involved in inflammatory response. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.094359994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD42	NM_001300975.2	c.736C>A	p.Gln246Lys	missense_variant	6/11	ENST00000533342.6
ANKRD42	NM_001300973.2	c.733C>A	p.Gln245Lys	missense_variant	6/12
ANKRD42	NM_001300972.2	c.736C>A	p.Gln246Lys	missense_variant	6/12
ANKRD42	NM_182603.4	c.652C>A	p.Gln218Lys	missense_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD42	ENST00000533342.6	c.736C>A	p.Gln246Lys	missense_variant	6/11	1	NM_001300975.2	A2
ANKRD42	ENST00000260047.10	c.733C>A	p.Gln245Lys	missense_variant	6/12	1		P2
ANKRD42	ENST00000531895.5	c.736C>A	p.Gln246Lys	missense_variant	6/12	1		A2
ANKRD42	ENST00000393392.6	c.652C>A	p.Gln218Lys	missense_variant	6/10	2

Frequencies

GnomAD3 genomes AF: 0.000244 AC: 37 AN: 151734 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000243 AC: 61 AN: 251236 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135794

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000263 AC: 384 AN: 1461068 Hom.: 0 Cov.: 31 AF XY: 0.000296 AC XY: 215 AN XY: 726870

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000318

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000244 AC: 37 AN: 151852 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74208

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000380 Hom.: 0

Bravo AF: 0.000238

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.00104

EpiControl AF: 0.000534

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The c.652C>A (p.Q218K) alteration is located in exon 6 (coding exon 6) of the ANKRD42 gene. This alteration results from a C to A substitution at nucleotide position 652, causing the glutamine (Q) at amino acid position 218 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	16
Dann	Benign	0.93
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.094	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.93	N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.050
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.72, 0.32	.;.;P;B
Vest4		0.48
MVP		0.38
MPC		0.22
ClinPred		0.038	T
GERP RS		3.5
Varity_R		0.14
gMVP		0.42

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: rs145605968; hg19: chr11-82936046;