dbSNP rs768877822: CSMD3:p.Gln3413His (chr8-112244557-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_198123.2(CSMD3):c.10239G>T(p.Gln3413His) 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 1,461,468 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CSMD3
NM_198123.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00700

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: 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_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.10239G>T	p.Gln3413His	missense	Exon 65 of 71	NP_937756.1	Q7Z407-1
CSMD3	NM_198124.2		c.10119G>T	p.Gln3373His	missense	Exon 66 of 72	NP_937757.1	Q7Z407-2
CSMD3	NM_052900.3		c.9732G>T	p.Gln3244His	missense	Exon 63 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.10239G>T	p.Gln3413His	missense	Exon 65 of 71	ENSP00000297405.5	Q7Z407-1
CSMD3	ENST00000343508.7	TSL:1	c.10119G>T	p.Gln3373His	missense	Exon 66 of 72	ENSP00000345799.3	Q7Z407-2
CSMD3	ENST00000455883.2	TSL:1	c.9732G>T	p.Gln3244His	missense	Exon 63 of 69	ENSP00000412263.2	Q7Z407-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251068

AF XY:

0.00000737

show subpopulations

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461468

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727062

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111706

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

0.037

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.7

PhyloP100

0.0070

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.34

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.71

MutPred

0.46

Gain of ubiquitination at K3412 (P = 0.0931)

MVP

0.69

MPC

0.34

ClinPred

0.99

GERP RS

-1.1

Varity_R

0.71

gMVP

0.57

Mutation Taster

=63/37

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over