chr2-197005906-A-G

Position:

• chr2-197005906-A-G

Variant summary

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

The NM_001195144.2(ANKRD44):​c.2135T>C​(p.Met712Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,812 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: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ANKRD44 NM_001195144.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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=0.39693332).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD44	NM_001195144.2	c.2135T>C	p.Met712Thr	missense_variant	21/28	ENST00000282272.15	NP_001182073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD44	ENST00000282272.15	c.2135T>C	p.Met712Thr	missense_variant	21/28	5	NM_001195144.2	ENSP00000282272	P4
ANKRD44	ENST00000424317.5	c.1580T>C	p.Met527Thr	missense_variant	15/22	1		ENSP00000403415
ANKRD44	ENST00000647377.1	c.2135T>C	p.Met712Thr	missense_variant	21/28			ENSP00000496628	A1
ANKRD44	ENST00000328737.6	c.2060T>C	p.Met687Thr	missense_variant	21/26	2		ENSP00000331516

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727208

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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

Sep 14, 2022

The c.2135T>C (p.M712T) alteration is located in exon 21 (coding exon 21) of the ANKRD44 gene. This alteration results from a T to C substitution at nucleotide position 2135, causing the methionine (M) at amino acid position 712 to be replaced by a threonine (T). 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	0.36
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	.;.;T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D;D;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.89	.;.;L;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.8	N;.;.;N
REVEL	Benign	0.24
Sift	Uncertain	0.0070	D;.;.;D
Sift4G	Benign	0.14	T;.;T;T
Vest4		0.55, 0.56
MVP		0.57
ClinPred		0.76	D
GERP RS		5.1
Varity_R		0.27
gMVP		0.34

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: rs771884805; hg19: chr2-197870630;