2-196993631-C-T

Variant names:

• chr2-196993631-C-T
• rs1414227313
• NM_001195144.2:c.2875G>A

Variant summary

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

The NM_001195144.2(ANKRD44):​c.2875G>A​(p.Glu959Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000786 in 1,398,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: ANKRD44 NM_001195144.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.29

Genes affected

ANKRD44 (HGNC:25259): (ankyrin repeat domain 44)

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=0.32462662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD44	NM_001195144.2	c.2875G>A	p.Glu959Lys	missense_variant	Exon 27 of 28	ENST00000282272.15	NP_001182073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD44	ENST00000282272.15	c.2875G>A	p.Glu959Lys	missense_variant	Exon 27 of 28	5	NM_001195144.2	ENSP00000282272.9
ANKRD44	ENST00000424317.5	c.2320G>A	p.Glu774Lys	missense_variant	Exon 21 of 22	1		ENSP00000403415.1
ANKRD44	ENST00000647377.1	c.2875G>A	p.Glu959Lys	missense_variant	Exon 27 of 28			ENSP00000496628.1
ANKRD44	ENST00000486006.1	n.8G>A		non_coding_transcript_exon_variant	Exon 1 of 2	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000786 AC: 11 AN: 1398766 Hom.: 0 Cov.: 31 AF XY: 0.00000435 AC XY: 3 AN XY: 689884

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: 0.00000927

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2875G>A (p.E959K) alteration is located in exon 27 (coding exon 27) of the ANKRD44 gene. This alteration results from a G to A substitution at nucleotide position 2875, causing the glutamic acid (E) at amino acid position 959 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	0.21
BayesDel_addAF	Benign	0.00029	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	.;.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.60	.;.;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.48	N;.;.
REVEL	Benign	0.18
Sift	Benign	0.20	T;.;.
Sift4G	Benign	0.47	T;.;T
Vest4		0.32
MVP		0.53
ClinPred		0.65	D
GERP RS		5.2
Varity_R		0.14
gMVP		0.32

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: rs1414227313; hg19: chr2-197858355;