2-68137403-T-G

Position:

• chr2-68137403-T-G

Variant summary

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

The NM_138458.4(DNAAF10):​c.664A>C​(p.Ile222Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAAF10 NM_138458.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.25

Genes affected

DNAAF10 (HGNC:25176): (dynein axonemal assembly factor 10) This gene encodes a protein with two WD40 repeat domains thought to be involved in an apoptosis via activation of caspase-3. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

ENSG00000273398 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27782047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF10	NM_138458.4	c.664A>C	p.Ile222Leu	missense_variant	6/8	ENST00000295121.11	NP_612467.1
DNAAF10	NM_001256476.2	c.664A>C	p.Ile222Leu	missense_variant	6/7		NP_001243405.1
DNAAF10	NR_046234.2	n.635A>C		non_coding_transcript_exon_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF10	ENST00000295121.11	c.664A>C	p.Ile222Leu	missense_variant	6/8	1	NM_138458.4	ENSP00000295121.6
ENSG00000273398	ENST00000406334.3	n.*681A>C		non_coding_transcript_exon_variant	13/15	2		ENSP00000384974.3
ENSG00000273398	ENST00000406334.3	n.*681A>C		3_prime_UTR_variant	13/15	2		ENSP00000384974.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460440 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726524

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

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

Oct 06, 2021

The c.664A>C (p.I222L) alteration is located in exon 6 (coding exon 6) of the WDR92 gene. This alteration results from a A to C substitution at nucleotide position 664, causing the isoleucine (I) at amino acid position 222 to be replaced by a leucine (L). 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	Uncertain	0.44
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.013	T;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	3.4	M;.;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.064	B;.;.
Vest4		0.38
MutPred		0.49		Loss of catalytic residue at L227 (P = 0.0366);.;Loss of catalytic residue at L227 (P = 0.0366);
MVP		0.45
MPC		0.33
ClinPred		0.94	D
GERP RS		6.0
Varity_R		0.44
gMVP		0.20

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: rs576876325; hg19: chr2-68364535;