Genetic Variant CSMD1:p.His3455Asn (chr8-2949338-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033225.6(CSMD1):c.10363C>A(p.His3455Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000311 in 1,607,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. H3455L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CSMD1
NM_033225.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.57

Publications

2 publications found

Variant links:

Genes affected

CSMD1 (HGNC:14026): (CUB and Sushi multiple domains 1) Predicted to act upstream of or within several processes, including learning or memory; mammary gland branching involved in pregnancy; and reproductive structure development. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

CSMD1 Gene-Disease associations (from GenCC):

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

CSMD1 links:

LOC105377785 (HGNC:):

LOC105377785 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14450774).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033225.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CSMD1	NM_033225.6	MANE Select	c.10363C>A	p.His3455Asn	missense	Exon 68 of 70	NP_150094.5
LOC105377785	NR_168441.1		n.1167-51667G>T		intron	N/A
LOC105377785	NR_168442.1		n.2191+22708G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSMD1	ENST00000635120.2	TSL:5 MANE Select	c.10363C>A	p.His3455Asn	missense	Exon 68 of 70	ENSP00000489225.1	Q96PZ7-1
CSMD1	ENST00000335551.11	TSL:1	c.8569C>A	p.His2857Asn	missense	Exon 54 of 56	ENSP00000334828.6	H7BXU2
CSMD1	ENST00000520002.5	TSL:5	c.10366C>A	p.His3456Asn	missense	Exon 69 of 71	ENSP00000430733.1	E5RIG2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151798

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:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000208

AC:

AN:

240492

AF XY:

0.0000229

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1455848

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724482

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33310

American (AMR)

AF:

0.00

AC:

AN:

44516

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26030

East Asian (EAS)

AF:

0.0000761

AC:

AN:

39432

South Asian (SAS)

AF:

0.00

AC:

AN:

85848

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108568

Other (OTH)

AF:

0.00

AC:

AN:

60140

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

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:

0.0000132

AC:

AN:

151798

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74116

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41358

American (AMR)

AF:

0.00

AC:

AN:

15202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2082

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

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

ExAC

AF:

0.00000828

AC:

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

-0.50

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.029

Eigen

Benign

0.054

Eigen_PC

Benign

0.057

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.59

M_CAP

Benign

0.0094

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.75

PhyloP100

4.6

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.5

REVEL

Benign

0.049

Sift

Benign

0.059

Sift4G

Uncertain

0.030

Polyphen

0.0010

Vest4

0.33

MutPred

0.32

Gain of ubiquitination at K3458 (P = 0.0662)

MVP

0.42

ClinPred

0.14

GERP RS

4.7

Varity_R

0.20

gMVP

0.43

Mutation Taster

=83/17

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