Genetic Variant NM_198529.4:c.611C>G (chr17-29969211-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.611C>G(p.Thr204Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,586 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: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

EFCAB5
NM_198529.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.503

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:

Genome browser will be placed here

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=0.028710425).

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.611C>G	p.Thr204Ser	missense	Exon 4 of 23	NP_940931.3	A4FU69-1
EFCAB5	NM_001145053.2		c.443C>G	p.Thr148Ser	missense	Exon 4 of 15	NP_001138525.2	A4FU69-5
EFCAB5	NR_026738.2		n.774C>G		non_coding_transcript_exon	Exon 4 of 16

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EFCAB5	ENST00000394835.8	TSL:1 MANE Select	c.611C>G	p.Thr204Ser	missense	Exon 4 of 23	ENSP00000378312.3	A4FU69-1
EFCAB5	ENST00000588978.1	TSL:1	c.5C>G	p.Thr2Ser	missense	Exon 1 of 12	ENSP00000465109.1	K7EJC3
EFCAB5	ENST00000440741.7	TSL:1	n.611C>G		non_coding_transcript_exon	Exon 4 of 16	ENSP00000393095.2	A4FU69-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461586

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727066

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111820

Other (OTH)

AF:

0.00

AC:

AN:

60366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000173310), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

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

0.13

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.11

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.0014

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.41

M_CAP

Benign

0.0025

MetaRNN

Benign

0.029

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.55

PhyloP100

-0.50

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.23

REVEL

Benign

0.0090

Sift

Benign

0.73

Sift4G

Benign

0.53

Polyphen

0.014

Vest4

0.081

MutPred

0.20

Loss of helix (P = 0.0093)

MVP

0.061

MPC

0.091

ClinPred

0.038

GERP RS

-1.7

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.024

gMVP

0.057

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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