Genetic Variant EFCAB5:p.Thr28Ser (chr17-29942280-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_198529.4(EFCAB5):c.83C>G(p.Thr28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 1,591,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

EFCAB5
NM_198529.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.304

Publications

0 publications found

Variant links:

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]

EFCAB5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056459576).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198529.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EFCAB5	NM_198529.4	MANE Select	c.83C>G	p.Thr28Ser	missense	Exon 2 of 23	NP_940931.3	A4FU69-1
EFCAB5	NM_001145053.2		c.-86C>G		5_prime_UTR	Exon 2 of 15	NP_001138525.2	A4FU69-5
EFCAB5	NR_026738.2		n.246C>G		non_coding_transcript_exon	Exon 2 of 16

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EFCAB5	ENST00000394835.8	TSL:1 MANE Select	c.83C>G	p.Thr28Ser	missense	Exon 2 of 23	ENSP00000378312.3	A4FU69-1
EFCAB5	ENST00000440741.7	TSL:1	n.83C>G		non_coding_transcript_exon	Exon 2 of 16	ENSP00000393095.2	A4FU69-2
EFCAB5	ENST00000536908.6	TSL:2	c.-86C>G		5_prime_UTR	Exon 2 of 15	ENSP00000440619.2	A4FU69-5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1439156

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

713534

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33032

American (AMR)

AF:

0.00

AC:

AN:

41420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25536

East Asian (EAS)

AF:

0.00

AC:

AN:

39126

South Asian (SAS)

AF:

0.00

AC:

AN:

81890

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1100508

Other (OTH)

AF:

0.00

AC:

AN:

59632

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.76

CADD

Benign

6.1

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.0026

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.25

M_CAP

Benign

0.0041

MetaRNN

Benign

0.056

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

PhyloP100

-0.30

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.030

REVEL

Benign

0.029

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.017

Vest4

0.054

MutPred

0.088

Gain of phosphorylation at T28 (P = 0.0797)

MVP

0.10

MPC

0.082

ClinPred

0.058

GERP RS

-1.5

Varity_R

0.043

gMVP

0.028

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over