Genetic Variant CSMD1:p.Asn1497Ser (chr8-3219437-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_033225.6(CSMD1):c.4490A>G(p.Asn1497Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,480,760 control chromosomes in the GnomAD database, including 13,111 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.11 ( 1172 hom., cov: 32)

Exomes 𝑓: 0.13 ( 11939 hom. )

Consequence

CSMD1
NM_033225.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.14

Publications

20 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001791805).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSMD1	NM_033225.6 link	c.4490A>G	p.Asn1497Ser	missense_variant	Exon 29 of 70	ENST00000635120.2	NP_150094.5	Q96PZ7-1Q59FF8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSMD1	ENST00000635120.2 link	c.4490A>G	p.Asn1497Ser	missense_variant	Exon 29 of 70	5	NM_033225.6	ENSP00000489225.1		Q96PZ7-1

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16340

AN:

152086

Hom.:

1169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0271

Gnomad AMI

AF:

0.0800

Gnomad AMR

AF:

0.168

Gnomad ASJ

AF:

0.0818

Gnomad EAS

AF:

0.0518

Gnomad SAS

AF:

0.0803

Gnomad FIN

AF:

0.178

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.140

Gnomad OTH

AF:

0.0944

GnomAD2 exomes

AF:

0.127

AC:

14070

AN:

110382

AF XY:

0.127

show subpopulations

Gnomad AFR exome

AF:

0.0272

Gnomad AMR exome

AF:

0.208

Gnomad ASJ exome

AF:

0.0820

Gnomad EAS exome

AF:

0.0528

Gnomad FIN exome

AF:

0.168

Gnomad NFE exome

AF:

0.136

Gnomad OTH exome

AF:

0.136

GnomAD4 exome

AF:

0.131

AC:

173863

AN:

1328556

Hom.:

11939

Cov.:

AF XY:

0.130

AC XY:

84264

AN XY:

650596

show subpopulations

African (AFR)

AF:

0.0210

AC:

595

AN:

28284

American (AMR)

AF:

0.191

AC:

4213

AN:

22054

Ashkenazi Jewish (ASJ)

AF:

0.0805

AC:

1690

AN:

20984

East Asian (EAS)

AF:

0.0561

AC:

1933

AN:

34432

South Asian (SAS)

AF:

0.0893

AC:

6179

AN:

69174

European-Finnish (FIN)

AF:

0.171

AC:

8185

AN:

47944

Middle Eastern (MID)

AF:

0.0959

AC:

448

AN:

4670

European-Non Finnish (NFE)

AF:

0.138

AC:

144237

AN:

1046204

Other (OTH)

AF:

0.116

AC:

6383

AN:

54810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

6472

12943

19415

25886

32358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5340

10680

16020

21360

26700

<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:

0.107

AC:

16352

AN:

152204

Hom.:

1172

Cov.:

AF XY:

0.109

AC XY:

8102

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0270

AC:

1123

AN:

41548

American (AMR)

AF:

0.168

AC:

2569

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0818

AC:

284

AN:

3472

East Asian (EAS)

AF:

0.0521

AC:

270

AN:

5178

South Asian (SAS)

AF:

0.0807

AC:

389

AN:

4818

European-Finnish (FIN)

AF:

0.178

AC:

1885

AN:

10592

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.140

AC:

9531

AN:

68002

Other (OTH)

AF:

0.0963

AC:

203

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

730

1459

2189

2918

3648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

178

356

534

712

890

<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:

0.117

Hom.:

2212

Bravo

AF:

0.102

TwinsUK

AF:

0.133

AC:

495

ALSPAC

AF:

0.138

AC:

530

ESP6500AA

AF:

0.0263

AC:

ESP6500EA

AF:

0.129

AC:

1058

ExAC

AF:

0.0903

AC:

10420

Asia WGS

AF:

0.0790

AC:

276

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.0090

T;.;.;.;T;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.88

D;.;D;D;.;D

MetaRNN

Benign

0.0018

T;T;T;T;T;T

MetaSVM

Benign

-0.97

PhyloP100

2.1

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.84

.;N;.;.;N;.

REVEL

Benign

0.13

Sift

Benign

0.76

.;T;.;.;T;.

Sift4G

Benign

0.73

T;T;T;T;T;T

Polyphen

0.0

.;.;.;.;B;B

Vest4

0.27, 0.27, 0.26, 0.14, 0.25

ClinPred

0.0012

GERP RS

3.0

Varity_R

0.049

gMVP

0.15

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: -1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over