14-89931629-G-A

Variant names:

• chr14-89931629-G-A
• rs757985158
• NM_145231.4:c.322C>T

Variant summary

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

The NM_145231.4(EFCAB11):​c.322C>T​(p.Arg108Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000383 in 1,460,682 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R108H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: EFCAB11 NM_145231.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85
• Publications: 2 publications found

Genes affected

EFCAB11 (HGNC:20357): (EF-hand calcium binding domain 11) Predicted to enable calcium ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000259053 (HGNC:):

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_145231.4. 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
	EFCAB11	NM_145231.4	MANE Select	c.322C>T	p.Arg108Cys	missense splice_region	Exon 5 of 6	NP_660274.1	Q9BUY7-1
	EFCAB11	NM_001284266.2		c.322C>T	p.Arg108Cys	missense splice_region	Exon 5 of 6	NP_001271195.1	Q9BUY7-5
	EFCAB11	NM_001284269.2		c.250C>T	p.Arg84Cys	missense splice_region	Exon 5 of 6	NP_001271198.1	Q9BUY7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFCAB11	ENST00000316738.12	TSL:2 MANE Select	c.322C>T	p.Arg108Cys	missense splice_region	Exon 5 of 6	ENSP00000326267.7	Q9BUY7-1
	EFCAB11	ENST00000555872.5	TSL:1	c.250C>T	p.Arg84Cys	missense splice_region	Exon 5 of 6	ENSP00000452320.1	Q9BUY7-2
	EFCAB11	ENST00000556005.1	TSL:1	c.250C>T	p.Arg84Cys	missense splice_region	Exon 5 of 6	ENSP00000452143.1	Q9BUY7-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250684 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1460682 Hom.: 0 Cov.: 29 AF XY: 0.0000372 AC XY: 27 AN XY: 726684

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1111258

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.9
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.31
MutPred		0.59		Gain of catalytic residue at D104 (P = 0.0049)
MVP		0.87
MPC		0.17
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.52
gMVP		0.65
Mutation Taster		=40/60	disease causing

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: rs757985158; hg19: chr14-90397973; COSMIC: COSV50860774;