Genetic Variant CSMD3:p.Ile3633Leu (chr8-112228823-T-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_198123.2(CSMD3):c.10897A>C(p.Ile3633Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,590,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

CSMD3
NM_198123.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.92

Publications

0 publications found

Variant links:

Genes affected

CSMD3 (HGNC:19291): (CUB and Sushi multiple domains 3) Predicted to be involved in regulation of dendrite development. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CSMD3 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CSMD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16155624).

BS2

High AC in GnomAdExome4 at 59 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198123.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSMD3	NM_198123.2	MANE Select	c.10897A>C	p.Ile3633Leu	missense	Exon 70 of 71	NP_937756.1	Q7Z407-1
CSMD3	NM_198124.2		c.10777A>C	p.Ile3593Leu	missense	Exon 71 of 72	NP_937757.1	Q7Z407-2
CSMD3	NM_052900.3		c.10390A>C	p.Ile3464Leu	missense	Exon 68 of 69	NP_443132.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSMD3	ENST00000297405.10	TSL:1 MANE Select	c.10897A>C	p.Ile3633Leu	missense	Exon 70 of 71	ENSP00000297405.5	Q7Z407-1
CSMD3	ENST00000343508.7	TSL:1	c.10777A>C	p.Ile3593Leu	missense	Exon 71 of 72	ENSP00000345799.3	Q7Z407-2
CSMD3	ENST00000455883.2	TSL:1	c.10390A>C	p.Ile3464Leu	missense	Exon 68 of 69	ENSP00000412263.2	Q7Z407-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

251012

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.0000410

AC:

AN:

1438416

Hom.:

Cov.:

AF XY:

0.0000390

AC XY:

AN XY:

717350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32698

American (AMR)

AF:

0.00

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25962

East Asian (EAS)

AF:

0.00

AC:

AN:

39410

South Asian (SAS)

AF:

0.00

AC:

AN:

85740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.0000504

AC:

AN:

1091346

Other (OTH)

AF:

0.0000671

AC:

AN:

59614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

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

Uncertain

0.50

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.039

Eigen

Benign

0.19

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.0048

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

2.9

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.73

REVEL

Benign

0.044

Sift

Benign

0.23

Sift4G

Benign

0.073

Polyphen

0.70

Vest4

0.64

MVP

0.35

MPC

0.20

ClinPred

0.21

GERP RS

5.7

Varity_R

0.22

gMVP

0.46

Mutation Taster

=66/34

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over