16-28477622-T-C

Variant names:

• chr16-28477622-T-C
• rs77595156
• NM_001042432.2:c.1211A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042432.2(CLN3):​c.1211A>G​(p.His404Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0549 in 1,613,844 control chromosomes in the GnomAD database, including 5,394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H404N) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1778 hom., cov: 33)
  • Exomes 𝑓: 0.049 (3616 hom.)
• Consequence: CLN3 NM_001042432.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.04
• Publications: 18 publications found

Genes affected

CLN3 (HGNC:2074): (CLN3 lysosomal/endosomal transmembrane protein, battenin) This gene encodes a protein that is involved in lysosomal function. Mutations in this, as well as other neuronal ceroid-lipofuscinosis (CLN) genes, cause neurodegenerative diseases commonly known as Batten disease or collectively known as neuronal ceroid lipofuscinoses (NCLs). Many alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

CLN3 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ENSG00000261832 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019387603).
• BP6: Variant 16-28477622-T-C is Benign according to our data. Variant chr16-28477622-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042432.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN3	NM_001042432.2	MANE Select	c.1211A>G	p.His404Arg	missense	Exon 16 of 16	NP_001035897.1
	CLN3	NM_000086.2		c.1211A>G	p.His404Arg	missense	Exon 15 of 15	NP_000077.1
	CLN3	NM_001286104.2		c.1139A>G	p.His380Arg	missense	Exon 15 of 15	NP_001273033.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN3	ENST00000636147.2	TSL:1 MANE Select	c.1211A>G	p.His404Arg	missense	Exon 16 of 16	ENSP00000490105.1
	CLN3	ENST00000359984.12	TSL:1	c.1211A>G	p.His404Arg	missense	Exon 15 of 15	ENSP00000353073.9
	CLN3	ENST00000565316.6	TSL:1	c.1160A>G	p.His387Arg	missense	Exon 14 of 14	ENSP00000456117.1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17161 AN: 152020 Hom.: 1771 Cov.: 33

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0631

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.0730

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0333

Gnomad OTH AF: 0.0858

GnomAD2 exomes AF: 0.0759 AC: 18997 AN: 250390 AF XY: 0.0749

Gnomad AFR exome AF: 0.281

Gnomad AMR exome AF: 0.0389

Gnomad ASJ exome AF: 0.0364

Gnomad EAS exome AF: 0.128

Gnomad FIN exome AF: 0.0719

Gnomad NFE exome AF: 0.0337

Gnomad OTH exome AF: 0.0471

GnomAD4 exome AF: 0.0488 AC: 71386 AN: 1461706 Hom.: 3616 Cov.: 31 AF XY: 0.0513 AC XY: 37282 AN XY: 727134

African (AFR) AF: 0.283 AC: 9491 AN: 33480

American (AMR) AF: 0.0404 AC: 1809 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0364 AC: 951 AN: 26136

East Asian (EAS) AF: 0.0987 AC: 3918 AN: 39700

South Asian (SAS) AF: 0.155 AC: 13346 AN: 86256

European-Finnish (FIN) AF: 0.0655 AC: 3489 AN: 53240

Middle Eastern (MID) AF: 0.0444 AC: 256 AN: 5766

European-Non Finnish (NFE) AF: 0.0311 AC: 34588 AN: 1112008

Other (OTH) AF: 0.0586 AC: 3538 AN: 60396

GnomAD4 genome AF: 0.113 AC: 17205 AN: 152138 Hom.: 1778 Cov.: 33 AF XY: 0.116 AC XY: 8625 AN XY: 74368

African (AFR) AF: 0.276 AC: 11461 AN: 41482

American (AMR) AF: 0.0629 AC: 962 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 126 AN: 3472

East Asian (EAS) AF: 0.123 AC: 637 AN: 5168

South Asian (SAS) AF: 0.159 AC: 768 AN: 4828

European-Finnish (FIN) AF: 0.0730 AC: 774 AN: 10600

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0332 AC: 2260 AN: 67984

Other (OTH) AF: 0.0878 AC: 185 AN: 2108

Alfa AF: 0.0542 Hom.: 1972

Bravo AF: 0.115

TwinsUK AF: 0.0305 AC: 113

ALSPAC AF: 0.0254 AC: 98

ESP6500AA AF: 0.269 AC: 1180

ESP6500EA AF: 0.0316 AC: 272

ExAC AF: 0.0807 AC: 9797

Asia WGS AF: 0.132 AC: 456 AN: 3478

EpiCase AF: 0.0318

EpiControl AF: 0.0290

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Neuronal ceroid lipofuscinosis 3 (2)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuronal ceroid lipofuscinosis (1)
-	-	1	Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.3	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.57
Sift	Benign	0.55	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.41
MPC		0.70
ClinPred		0.017	T
GERP RS		5.0
Varity_R		0.42
gMVP		0.54
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs77595156; hg19: chr16-28488943; COSMIC: COSV61107434; COSMIC: COSV61107434;