rs374714449

Variant names:

• chr8-100529794-C-A
• rs374714449
• NM_001270377.2:c.40G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-100529794-C-A
• chr8-100529794-C-G
• chr8-100529794-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001270377.2(ANKRD46):​c.40G>T​(p.Val14Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V14M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ANKRD46 NM_001270377.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.57
• Publications: 0 publications found

Genes affected

ANKRD46 (HGNC:27229): (ankyrin repeat domain 46) This gene encodes a protein containing multiple ankyrin repeats. Ankyrin domains function in protein-protein interactions in a variety of cellular processes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270377.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD46	NM_001270377.2	MANE Select	c.40G>T	p.Val14Leu	missense	Exon 3 of 5	NP_001257306.1	Q86W74-2
	ANKRD46	NM_001270379.2		c.40G>T	p.Val14Leu	missense	Exon 3 of 6	NP_001257308.1	Q86W74-1
	ANKRD46	NM_001270378.2		c.40G>T	p.Val14Leu	missense	Exon 3 of 5	NP_001257307.1	Q86W74-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD46	ENST00000335659.7	TSL:1 MANE Select	c.40G>T	p.Val14Leu	missense	Exon 3 of 5	ENSP00000335287.3	Q86W74-2
	ANKRD46	ENST00000520552.5	TSL:1	c.40G>T	p.Val14Leu	missense	Exon 3 of 6	ENSP00000429015.1	Q86W74-1
	ANKRD46	ENST00000519597.5	TSL:1	c.40G>T	p.Val14Leu	missense	Exon 4 of 6	ENSP00000430056.1	Q86W74-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0020	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.55	N
PhyloP100		5.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.44	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.022	D
Sift4G	Benign	0.21	T
Polyphen		0.93	P
Vest4		0.71
MutPred		0.60		Loss of catalytic residue at V14 (P = 0.076)
MVP		0.57
MPC		0.95
ClinPred		0.60	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.75
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs374714449; hg19: chr8-101542022;