17-29969327-G-A

Position:

• chr17-29969327-G-A

Variant summary

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

The NM_198529.4(EFCAB5):​c.727G>A​(p.Glu243Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,478 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: EFCAB5 NM_198529.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.05

Genes affected

EFCAB5 (HGNC:24801): (EF-hand calcium binding domain 5) Predicted to enable calcium ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

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=0.31419137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFCAB5	NM_198529.4	c.727G>A	p.Glu243Lys	missense_variant	4/23	ENST00000394835.8	NP_940931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFCAB5	ENST00000394835.8	c.727G>A	p.Glu243Lys	missense_variant	4/23	1	NM_198529.4	ENSP00000378312	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456478 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724352

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

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

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

Jan 23, 2023

The c.727G>A (p.E243K) alteration is located in exon 4 (coding exon 4) of the EFCAB5 gene. This alteration results from a G to A substitution at nucleotide position 727, causing the glutamic acid (E) at amino acid position 243 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	0.14
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	.;T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	.;M;.
MutationTaster	Benign	0.61	D;D;D;D;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.10	T;T;D
Sift4G	Pathogenic	0.0	D;T;T
Polyphen		0.95	.;P;.
Vest4		0.41
MutPred		0.38		.;Gain of MoRF binding (P = 0.0093);.;
MVP		0.57
MPC		0.31
ClinPred		0.96	D
GERP RS		4.3
Varity_R		0.17
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1454006521; hg19: chr17-28296345;