Genetic Variant CSMD1:p.Pro3469Ala (chr8-2942602-G-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_033225.6(CSMD1):c.10405C>G(p.Pro3469Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,567,484 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.00081 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 40 hom. )

Consequence

CSMD1
NM_033225.6 missense, splice_region

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.17

Publications

0 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034969747).

BP6

Variant 8-2942602-G-C is Benign according to our data. Variant chr8-2942602-G-C is described in ClinVar as Benign. ClinVar VariationId is 3045826.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000808 (123/152296) while in subpopulation SAS AF = 0.0243 (117/4824). AF 95% confidence interval is 0.0207. There are 5 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

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.10405C>G	p.Pro3469Ala	missense splice_region	Exon 69 of 70	NP_150094.5
LOC105377785	NR_168441.1		n.1167-58403G>C		intron	N/A
LOC105377785	NR_168442.1		n.2191+15972G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSMD1	ENST00000635120.2	TSL:5 MANE Select	c.10405C>G	p.Pro3469Ala	missense splice_region	Exon 69 of 70	ENSP00000489225.1	Q96PZ7-1
CSMD1	ENST00000335551.11	TSL:1	c.8611C>G	p.Pro2871Ala	missense splice_region	Exon 55 of 56	ENSP00000334828.6	H7BXU2
CSMD1	ENST00000520002.5	TSL:5	c.10408C>G	p.Pro3470Ala	missense splice_region	Exon 70 of 71	ENSP00000430733.1	E5RIG2

Frequencies

GnomAD3 genomes

AF:

0.000808

AC:

123

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0242

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00313

AC:

575

AN:

183730

AF XY:

0.00407

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000798

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000751

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000128

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00135

AC:

1911

AN:

1415188

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

1372

AN XY:

700220

show subpopulations

African (AFR)

AF:

0.0000624

AC:

AN:

32060

American (AMR)

AF:

0.000109

AC:

AN:

36704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24976

East Asian (EAS)

AF:

0.00

AC:

AN:

38044

South Asian (SAS)

AF:

0.0222

AC:

1786

AN:

80626

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51148

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.00000736

AC:

AN:

1087278

Other (OTH)

AF:

0.00177

AC:

104

AN:

58684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

169

254

338

423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.000808

AC:

123

AN:

152296

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41560

American (AMR)

AF:

0.000131

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.0243

AC:

117

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000128

Hom.:

Bravo

AF:

0.000196

ExAC

AF:

0.00295

AC:

347

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

CSMD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

6.4

(source)

DANN

Benign

0.095

DEOGEN2

Benign

0.010

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.0

PhyloP100

3.2

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.98

REVEL

Benign

0.037

Sift

Benign

0.091

Sift4G

Benign

0.61

Polyphen

0.0020

Vest4

0.16

MutPred

0.24

Loss of disorder (P = 0.0756)

MVP

0.41

ClinPred

0.019

GERP RS

3.9

Varity_R

0.062

gMVP

0.19

Mutation Taster

=100/0

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