rs41269019

Variant names:

• chr9-19290796-A-C
• rs41269019
• NM_001330640.2:c.721A>C

Your query was ambiguous. Multiple possible variants found:

• chr9-19290796-A-C
• chr9-19290796-A-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001330640.2(DENND4C):​c.721A>C​(p.Ile241Leu) variant causes a missense change. The variant allele was found at a frequency of 0.027 in 1,612,498 control chromosomes in the GnomAD database, including 684 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I241V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (40 hom., cov: 32)
  • Exomes 𝑓: 0.028 (644 hom.)
• Consequence: DENND4C NM_001330640.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.28
• Publications: 9 publications found

Genes affected

DENND4C (HGNC:26079): (DENN domain containing 4C) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in cellular response to insulin stimulus; protein localization to plasma membrane; and regulation of Rab protein signal transduction. Located in Golgi apparatus and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055373907).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0195 (2973/152284) while in subpopulation NFE AF = 0.0315 (2142/68004). AF 95% confidence interval is 0.0304. There are 40 homozygotes in GnomAd4. There are 1328 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND4C	NM_001330640.2	c.721A>C	p.Ile241Leu	missense_variant	Exon 5 of 33	ENST00000434457.7	NP_001317569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND4C	ENST00000434457.7	c.721A>C	p.Ile241Leu	missense_variant	Exon 5 of 33	5	NM_001330640.2	ENSP00000473469.1
DENND4C	ENST00000494124.2	n.37A>C		non_coding_transcript_exon_variant	Exon 1 of 28	1		ENSP00000473273.1
DENND4C	ENST00000602925.5	c.721A>C	p.Ile241Leu	missense_variant	Exon 5 of 32	5		ENSP00000473565.1
DENND4C	ENST00000380437.8	n.39A>C		non_coding_transcript_exon_variant	Exon 1 of 29	5

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2971 AN: 152164 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00562

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.0253

GnomAD2 exomes AF: 0.0189 AC: 4706 AN: 248942 AF XY: 0.0188

Gnomad AFR exome AF: 0.00517

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00785

Gnomad NFE exome AF: 0.0310

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0277 AC: 40516 AN: 1460214 Hom.: 644 Cov.: 30 AF XY: 0.0269 AC XY: 19563 AN XY: 726378

African (AFR) AF: 0.00466 AC: 156 AN: 33444

American (AMR) AF: 0.0134 AC: 599 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 547 AN: 26084

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39600

South Asian (SAS) AF: 0.00537 AC: 462 AN: 86028

European-Finnish (FIN) AF: 0.00906 AC: 483 AN: 53334

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5758

European-Non Finnish (NFE) AF: 0.0332 AC: 36874 AN: 1111058

Other (OTH) AF: 0.0227 AC: 1369 AN: 60280

GnomAD4 genome AF: 0.0195 AC: 2973 AN: 152284 Hom.: 40 Cov.: 32 AF XY: 0.0178 AC XY: 1328 AN XY: 74486

African (AFR) AF: 0.00561 AC: 233 AN: 41548

American (AMR) AF: 0.0195 AC: 299 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4828

European-Finnish (FIN) AF: 0.00678 AC: 72 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0315 AC: 2142 AN: 68004

Other (OTH) AF: 0.0250 AC: 53 AN: 2116

Alfa AF: 0.0262 Hom.: 197

Bravo AF: 0.0199

TwinsUK AF: 0.0375 AC: 139

ALSPAC AF: 0.0350 AC: 135

ESP6500AA AF: 0.00707 AC: 26

ESP6500EA AF: 0.0294 AC: 241

ExAC AF: 0.0194 AC: 2350

Asia WGS AF: 0.00231 AC: 8 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-0.87	T
PhyloP100		6.3
PrimateAI	Uncertain	0.59	T
Sift4G	Benign	0.27	T;T
Vest4		0.22
MPC		0.17
ClinPred		0.0098	T
GERP RS		5.4
Varity_R		0.17
gMVP		0.52
Mutation Taster		=71/29	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41269019; hg19: chr9-19290794; COSMIC: COSV107501463; COSMIC: COSV107501463;