7-16610615-C-G

Variant names:

• chr7-16610615-C-G
• rs1403566645
• NM_020319.3:c.680G>C

Variant summary

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

The NM_020319.3(ANKMY2):​c.680G>C​(p.Cys227Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ANKMY2 NM_020319.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

ANKMY2 (HGNC:25370): (ankyrin repeat and MYND domain containing 2) Predicted to enable enzyme binding activity and metal ion binding activity. Predicted to be located in cilium. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000287799 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKMY2	NM_020319.3	c.680G>C	p.Cys227Ser	missense_variant	Exon 6 of 10	ENST00000306999.7	NP_064715.1
LOC105375169	XR_007060225.1	n.88-2524C>G		intron_variant	Intron 1 of 4
LOC105375169	XR_007060226.1	n.88-2524C>G		intron_variant	Intron 1 of 4
LOC105375169	XR_007060227.1	n.81-5411C>G		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKMY2	ENST00000306999.7	c.680G>C	p.Cys227Ser	missense_variant	Exon 6 of 10	1	NM_020319.3	ENSP00000303570.2
ANKMY2	ENST00000628652.1	c.680G>C	p.Cys227Ser	missense_variant	Exon 6 of 9	5		ENSP00000485738.1
ANKMY2	ENST00000447802.3	n.680G>C		non_coding_transcript_exon_variant	Exon 6 of 11	2		ENSP00000392259.1
ENSG00000287799	ENST00000663260.1	n.224-2524C>G		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251260 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461612 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727114

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.680G>C (p.C227S) alteration is located in exon 6 (coding exon 6) of the ANKMY2 gene. This alteration results from a G to C substitution at nucleotide position 680, causing the cysteine (C) at amino acid position 227 to be replaced by a serine (S). 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	0.19
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.7	D;.
REVEL	Uncertain	0.53
Sift	Benign	0.43	T;.
Sift4G	Benign	0.43	T;T
Polyphen		0.11	B;.
Vest4		0.86
MutPred		0.51		Loss of ubiquitination at K231 (P = 0.1264);Loss of ubiquitination at K231 (P = 0.1264);
MVP		0.76
MPC		0.057
ClinPred		0.46	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1403566645; hg19: chr7-16650240; COSMIC: COSV105126657;